Interstate 10 (I-10) is the southernmost transcontinental highway in the Interstate Highway System of the United States. It stretches from the Pacific Ocean at State Route 1 (Pacific Coast Highway) in Santa Monica, California to Interstate 95 in Jacksonville, Florida. The freeway is part of the original Interstate Highway plans designated in 1956 with its final section completed in 1990. Over one third of the length of I-10 resides in the state of Texas where the freeway spans the state at its widest points.

Between its west terminus in Santa Monica, California and the East Los Angeles Interchange it is known as the Santa Monica Freeway. The Santa Monica Freeway is also called the "Rosa Parks Freeway" for the segment beginning at I-405 (the San Diego Freeway), and ending at I-110 / State Route 110 (the Harbor Freeway); either name can be used when referring to this stretch of road. The segment between the East Los Angeles Interchange and the city of San Bernardino, California, 63 miles (101 km) long, is known as the San Bernardino Freeway. Other names exist for I-10. For example, a sign near the western terminus of the highway (in Santa Monica, California) announces it as the Christopher Columbus Transcontinental Highway. It is known to a considerably lesser degree as the "Veterans Memorial Highway", and it is listed as a Blue Star Memorial Highway. In Palm Springs, I-10 is also signed as the Sonny Bono Memorial Freeway as a tribute to the late entertainer who served both as mayor and as a United States Congressman. Another stretch a short distance east in Indio is signed as the Doctor June McCarroll Memorial Freeway.

In Arizona, the highway is designated the Pearl Harbor Memorial Highway. The portion through Phoenix is named the Papago Freeway and is a vital piece of the regional freeway system. This designation starts at AZ Loop 101, near 99th Avenue, and runs eastward to the interchange southeast of downtown which is the terminus of I-17.

From the southern terminus of Interstate 17 to the junction with AZ Loop 202, the highway is signed as the Maricopa Freeway. This name holds true as well for I-17 from its southern terminus to its second junction with I-10, north of McDowell Road. From Loop 202 south to I-8's eastern terminus just southeast of Casa Grande, the highway is signed as the "Pearl Harbor Memorial Highway". ADOT also has maps that show it as the Maricopa Freeway, while AAA and other sources show it as the Pima Freeway. The latter's name is used on a stretch of Loop 101 from Loop 202 to Interstate 17.

Between Interstate 17 in Phoenix and the Interstate 19 interchange in Tucson, I-10 is included in the federally-designated CANAMEX corridor, extending from Mexico City to Edmonton, Alberta.

In Tucson, Arizona, between I-10 mileposts 259 and 260 are interchange ramps connecting I-10 with the northern terminus of Interstate 19.

The highest elevation in the US along I-10 occurs east of Tucson, 20 miles west of Wilcox, at the mile marker 320 exit for the Amerind Foundation and Museum. The west-bound lanes of I-10 briefly cross above 5000 ft.

Interstate 10 in New Mexico more or less follows the former path of U.S. Route 80 across the state, although major portions of old US 80 were bypassed in Western New Mexico's Bootheel and in Doña Ana County. Only three cities of significant size are located on the interstate: Lordsburg, Deming, and Las Cruces. Most of I-10 in New Mexico, between Exit 24 and Exit 135, is concurrent with U.S. Route 70.

At Lordsburg is the western junction of U.S. Route 70 and a concurrency; the two highways are joined all the way to Las Cruces. Several exits between Lordsburg and Deming are either for former towns (including Separ, Quincy, and Gage) or lack any town at all.

At Deming is the western junction of U.S. Route 180, which also forms a concurrency with I-10 all the way to El Paso. One mile (1.6 km) north of Deming on US 180 is New Mexico State Road 26 which serves as a short cut to north I-25 and Albuquerque.

I-10/US 70/US 180 continue east to Las Cruces which is the southern end of Interstate 25. US 70 leaves Interstate 10 (prior to the junction with I-25), heading northeast to Alamogordo, passing through the north side of Las Cruces. The junction with I-25 occurs just south of the New Mexico State University campus, on the southern end of Las Cruces. I-10/US 180 becomes concurrent with U.S. Route 85 at the junction with I-25. I-10/US 85/US 180 then turns south to the Texas state line, crossing it at Anthony.

From the state line with New Mexico to State Highway 20 in west El Paso, I-10 is bordered by frontage roads South Desert for lanes along I-10 East (actually headed south) and North Desert for lanes along I-10 West (headed north). The interstate then has no frontage roads for 9 miles (14 km) but regains them east of downtown and retains them to Clint. In this stretch, the frontage roads are Gateway East for the eastbound lanes and Gateway West for the westbound lanes. All four frontage roads are one way streets. Gateway East and Gateway West are notable, in particular, for TxDOT's liberal usage of the Texas U-turn at most underpasses of I-10 on this stretch.

A small portion of I-10 from Loop 1604 to Downtown San Antonio is known as the Northwest Expressway or the McDermott Freeway, while another portion from downtown to Loop 1604 East is called East Expressway or José López Freeway.

In Houston, from the western suburb of Katy to downtown, I-10 is known as the Katy Freeway. This section has as many as 26 lanes (12 mainlanes, 8 lanes of access roads, and 6 mid-freeway HOT/HOV lanes, not counting access road turning lanes) and is one of the widest freeways in the world. The space for the expansion was the right-of-way of the old Missouri-Kansas-Texas Railroad. The section east of downtown Houston is officially known as the East Freeway, although it is widely known by locals as the Baytown East Freeway due to a marketing push by Baytown, one of the largest cities in the Greater Houston Area.

In Beaumont, it is known as I-10 South, south of Calder Avenue, and I-10 North, north of Calder Avenue. It is known as I-10 East from the I-10 curve to the Neches River, which is Beaumont's and Jefferson County's eastern boundary line. Orange County is on the other side.

In Louisiana, an 18-mile (29 km) stretch of elevated highway between Lafayette and Baton Rouge is known as the Atchafalaya Swamp Freeway, as it goes over the Atchafalaya River, across the Atchafalaya Basin Bridge, and the adjacent swamps. It crosses the Mississippi River at the Horace Wilkinson Bridge. In Lake Charles, a 13-mile (21 km) loop route signed as I-210 branches off of I-10 and goes through the southern portion of the city. Interstate 12 links Baton Rouge to Slidell and bypasses Interstate 10's southward jog through New Orleans by remaining north of Lake Pontchartrain. In New Orleans, a stretch of I-10 from the I-10/I-610 Junction near the Orleans-Jefferson parish line to the U.S. Route 90 / U.S. Route 90 Business Junction is known as the Pontchartrain Expressway. A dip near the I-10/I-610 Junction to travel under a railroad track is one of the lowest points in New Orleans, and is highly susceptible to flooding. Pictures of water dozens of feet deep during Hurricane Katrina are commonplace. Near Slidell, the final stretch of I-10 through the Mississippi state line is known as the Stephen Ambrose Memorial Highway.

I-310 and I-510 are parts of what was slated to be I-410 and act as a southern bypass of New Orleans. I-610 is a shortcut from the eastern to western portion of New Orleans avoiding I-10's detour into New Orleans' Central Business District.

Interstate 10 in Mississippi runs from the Louisiana state line to the Alabama state line through Hancock, Harrison and Jackson counties on the Gulf Coast. It passes through the northern sections of Gulfport and Biloxi while passing just north of Pascagoula and Bay St. Louis. It also passes right south of the Stennis Space Center. The highway roughly parallels U.S. Route 90.

The law defining the route of Interstate 10 is Mississippi Code § 65-3-3.

I-10 crosses from Jackson County, Mississippi and goes through Mobile County in Southwest Alabama. In Mobile, the highway is the southern terminus for Interstate 65. In downtown Mobile, I-10 goes through one of the few road tunnels in Alabama, the George C. Wallace Tunnel under the Mobile River. The eastbound approach is posted at 40 miles per hour (64 km/h) because of the sharp curve approaching the tunnel. The highway then crosses approximately 8 miles (13 km) of the upper part of Mobile Bay on the Jubilee Parkway, a bridge locals refer to as the Bayway. It is next to Battleship Parkway. On the other side of Mobile Bay, the highway goes through the suburban "Eastern Shore" area of Baldwin County before passing through Malbis, Loxley and on to the Perdido River to cross into Florida.

Most of Interstate 10 in Florida travels through some of the least-populated areas in the state. Consequently, much of I-10 west of Interstate 295 in Jacksonville has only 4 lanes. In Pensacola, an approximately 3-mile (4.8 km) stretch of I-10 was widened to 6 lanes in 2008. That project is now completed. In Tallahassee, construction was completed in June 2009 on a project to widen an approximately 8-mile (13 km) stretch of I-10 to six lanes.

In Jacksonville, as in Arizona, I-10 is designated as Pearl Harbor Memorial Highway. Throughout much of Florida, Interstate 10 is also State Road 8, though it is not signed as such. (Where I-110 in Pensacola, Florida, is known as State Road 8A.)

Florida and Alabama are currently planning a possible connector that would link Dothan, Alabama, with I-10. Initial plans are calling for making this new highway a toll road, and it could be a reality within five years. As of May 2008, it is unknown which number this new road will be assigned.

In Tucson, AZ all exits between Prince Road and 22nd Street are being reopened after an extensive, three-year improvement project. I-10 has been being widened from six to eight lanes, and seven bridges and underpasses have been built to deal with congestion. Plans are also under way to widen I-10 from Marana north to the I-8 interchange at Casa Grande from 4 lanes to 6 lanes starting in the later half of 2007 and continuing into 2008 and 2009.

Texas formerly shared the highest speed limit in the nation with Utah's test section of I-15. The speed limit along I-10 from Kerr County to El Paso County was raised by the Texas Legislature to 75 miles per hour (121 km/h) in 1999 and to 80 miles per hour (130 km/h) in 2006. However, the nighttime maximum speed limit remained 65 miles per hour (105 km/h) and the daytime truck speed limit was 70 miles per hour (110 km/h). With 70,000 miles (110,000 km) of highway in Texas the 432-mile (695 km) stretch of Interstate 10, and 89 miles (143 km) of Interstate 20, between Monahans and the I-10 interchange at the cusp of the Jeff Davis Mountains, only a small percentage of roads were affected.

On September 1, 2011, night-time speed limits were eliminated and the statutory maximum speed limit in Texas was increased from 80 to 85 mph, although no 85 mph speed zones have yet been established.