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Williams' rushing total was the most for a player in his first game at the Sooners' home field, and he became only the fourth player at the school to eclipse 100 yards rushing in each of his first two games. Adrian Peterson was the last to do it, in 2004.
Landry Jones threw for 252 yards and two touchdowns with one interception for the Sooners (2-0), who had dropped a spot in the rankings after an unimpressive 24-7 victory in their opener at UTEP.
Travis Harvey caught a 75-yard touchdown pass from Damien Fleming and finished with 118 yards receiving for Florida A&M (0-2) of the Football Championship Subdivision.
Chase Varnadore hit field goals from 41 and 46 yards for the Rattlers, who fell to 0-14 against FBS foes since beating Miami in 1979.
Williams surpassed the record set just last year by Dominique Whaley in his Owen Field debut, running for 136 yards in last season's opener against Tulsa. The junior college transfer who was brought in after Oklahoma had three running backs transfer out of the program last season has turned into an instant star.
He had the clinching 65-yard touchdown run in the fourth quarter of last week at UTEP, and one-upped that by dashing 89 yards untouched for a score in the third quarter. That tied for the seventh-longest run in Oklahoma history.
It was part of a proficient second half for the Sooners, who used their depth to wear down the Rattlers on the ground. Brennan Clay added a pair of touchdown runs, from 3 and 10 yards, and Whaley and Roy Finch ran for scores after Jones got pulled for the last drive of the third quarter.
Oklahoma racked up 278 yards rushing in the second half, with 217 in the third quarter alone.
Starting free safety Tony Jefferson hopped off the field on only his left leg late in the first quarter and did not return. He was on the sideline in the second half with a cast on his right foot.
Jones notched his 31st victory, surpassing Jamelle Holieway for second in school history. He can tie Steve Davis' record when the Sooners host No. 21 Kansas State on Sept. 22, after a week off.
Penn State transfer Justin Brown played a big role in Oklahoma zipping out to a 28-3 second-quarter lead, setting up two of the Sooners' scores with long punt returns that brought the ball inside the 10-yard line. Williams pushed and twisted his way in from 4 yards out to cash in the first one, and Stills leaped to catch a 16-yard touchdown pass from Jones on the other, one play after Jones had been sacked.
Williams also had touchdown runs from 3 and 15 yards.
Oklahoma's home opener had a few more hiccups than usual against an FCS foe. Under Bob Stoops, the Sooners had outscored their only three other FCS opponents by a collective margin of 170-2.
This time, the dominance wasn't quite so complete.
Jones threw an interception to Devan Roberts, who dropped another potential pick that hit him right in the hands, and Whaley fumbled for the third time in two games. This time, the other team pounced on it and it led to Varnadore's 41-yard field goal.
After Harvey's 75-yard catch and run, Oklahoma answered right back with an 87-yard drive and Jones connected with Trey Metoyer on an 18-yard TD toss with 36 seconds left before halftime.