The pickup truck burst into flames, and the driver was declared dead at the scene on Interstate 10 in Casa Grande, about 50 miles south of Phoenix. Authorities couldn't immediately say if he died on impact or in the ensuing fire.
None of the passengers on the bus suffered life-threatening injuries, said Capt. Brian Preston of the Arizona Department of Public Safety.
"Generally when you have a vehicle going the wrong way on an interstate, you'd think it would be much worse than this," Preston said.
DPS spokesman Bart Graves said authorities received several 911 calls just before 2:15 p.m. about a driver on the main route from Phoenix to Tucson travelling east in the westbound lanes.
"We were responding when the accident occurred," said Graves, adding that the name of the driver wasn't immediately available.
Preston said the man was in his 70s, and that investigators will be working to determine whether drugs or alcohol were a factor.
The fiery crash closed the westbound lanes of I-10 near Interstate 8 for hours, backing up traffic for miles until one lane was reopened Tuesday evening. The bus still sat on the side of the freeway, its front end crumpled from the impact and several windows blown out.
Graves said the TBC Conexion bus from Mexico was headed to Phoenix with 16 people aboard, including the driver.
The driver, who was conscious and walking around when authorities arrived, was among two people who were seriously injured and airlifted from the scene to a Phoenix hospital, Preston said. Seven passengers on the bus were taken by ground ambulance to Casa Grande-area hospitals with injuries authorities described as minor to moderate.
The identities of the injured weren't immediately released. Calls to TBC Conexion's offices in Phoenix and Tucson weren't immediately returned Tuesday evening.
Graves said an 18-wheeler jackknifed at the accident scene and hit the side of the bus, but the main damage was done by the pickup truck. The driver of the tractor-trailer wasn't injured.