I8 enters Arizona from California at the Colorado River bridge at Yuma. It initially heads south through Yuma until the interchange with US 95, where the freeway begins to turn to the east and passes through eastern Yuma and Fortuna Foothills, briefly paralleling US 95. West of Wellton, the highway takes a northeasterly course, paralleling the Gila River and passing to the south of Roll. Through this part of Arizona, I8 passes along the northern edge of the Barry M. Goldwater Air Force Range and to the south of the Yuma Proving Ground. It keeps a northeastern heading, passing through the community of Dateland, until it reaches Gila Bend. There, the freeway intersects SR 85 heading north to Phoenix and south to the Organ Pipe Cactus National Monument.[2][25]

After leaving Gila Bend, I8 takes a southeastern course as it passes through the Sonoran Desert National Monument. Exiting the national monument grounds, the highway continues on an easterly bearing to a junction with SR 84, a highway that parallels I8 to the north and goes through Casa Grande, while I8 passes to the south of both Stanfield and Casa Grande. I8 reaches its eastern terminus southeast of Casa Grande Mountain Park at an interchange with I10, which continues south to Tucson, and north to Phoenix.[2][25]

The combination of SR 85 between I10 and I8 as well as I8 between SR 85 and I10 in Casa Grande has been promoted as a bypass of the Phoenix area for longdistance travelers on I10.[26] In 2013, I8 had an AADT of 5,100 between Butterfield Trail and Freeman Road, and 41,400 between SR 280 and Araby Road east of Yuma, the latter of which was the highest AADT for the highway in Arizona.[27] In the early 2010s, I8 from Casa Grande to Gila Bend was sometimes used for smuggling both drugs and humans