The Rebels hosted SEC opponents Vanderbilt, Kentucky, Auburn and Mississippi State and travelled to Alabama, Arkansas, Tennessee and LSU.

The Rebels played host to the Ragin Cajuns of Louisiana Lafayette for their homecoming game on November 6.

The Ole Miss Rebels began their 2010 football season playing FCS opponent Jacksonville State.

The Rebels got off to a hot start with Sophomore quarterback Nathan Stanley throwing two long touchdown passes, and would later add a third in the second quarter.

A 70-yard touchdown pass from newly named starting quarterback Jeremiah Masoli gave the Rebels a 24–3 lead at halftime.

Despite ten unanswered points from the Green Wave, the Rebels won the game 27–13 giving them their first victory of the season.

The Rebels hosted the Vanderbilt Commodores in their SEC opener, who had lost 10 straight games within the Southeastern Conference.

After a scoreless first quarter, Vanderbilt running back Zac Stacy rushed for a 35-yard touchdown to put the Commodores ahead 7–0.

A Masoli interception with 1:50 remaining would seal the win for Vanderbilt, their second consecutive victory at Vaught–Hemingway Stadium.

An interception by Mark Barron in the fourth quarter ended the Rebels' chances as they fell to the defending champions 23–10.

Despite the loss, the Rebels defense played their best game of the season as they allowed just 100 rushing yards by Mark Ingram II and Trent Richardson, and sacked Greg McElroy 5 times.

Following a 30-minute lightning delay, Masoli hooked up with Markeith Summers for a 43-yard touchdown pass to cut to Razorback lead 24–17.

Despite a valiant effort to come back, the Rebels' defense could not gather themselves as they gave up a 22-yard touchdown run by Knile Davis to put the game away.

Starting quarterback Jeremiah Masoli had to leave the game with a concussion, and Sophomore Nathan Stanley took over as starter.