Nebraska lost its workhorse running back Rex Burkhead in the second quarter, but junior quarterback Taylor Martinez picked up the slack.
Martinez threw for a career-high 354 yards and five touchdowns on 26-of-34 efficiency as No. 17 Nebraska pulled away from Southern Miss, 49-20, and extended its nation's longest active winning streak in season openers to 27.
"I thought he played very well, very efficient," Nebraska head coach Bo Pelini said of Martinez's performance. "(He) made good decisions, and he distributed the ball well. I thought there were a lot of positives there."
Burkhead, who ran for 1,357 yards and 15 touchdowns last season, carried the ball three times for 68 yards, including a 57-yard touchdown run in the opening frame, before exiting with a left knee injury.
"He'll be fine. He's day-to-day, week-to-week. I don't think it's anything long term," Pelini said of the injury.
Burkhead's backup, Ameer Abdullah, racked up 81 yards rushing on 15 carries, while Braylon Heard added 34 yards on the ground with a score for the Cornhuskers (1-0), who went 9-4 a year ago and finished third in the Legends division of the Big Ten.
Kyler Reed, Jake Long, Steven Osborne, Kenny Bell and Abdullah each caught a TD pass.
Chris Campbell was 6-of-12 for 69 yards and a score in Ellis Johnson's head coaching debut for the Golden Eagles (0-1), who won a school-record 12 games a year ago.
Johnson, who spent the last four seasons as the defensive coordinator at South Carolina, took over for Larry Fedora, now the head coach at North Carolina.
"We've just got to get better. We are not that tough on defense," Johnson said.
Burkhead got up slowly and gingerly before limping to the sidelines following a nine-yard run with a little more than six minutes left in the second.
Nebraska led, 14-7, at that point, but the Golden Eagles concluded an 11-play, 73-yard march on their ensuing possession when Campbell found Dominique Sullivan for a 24-yard TD strike, which knotted the contest late in the second.
But the Cornhuskers, guided by an accurate and efficient Martinez, outscored Southern Miss 35-6 the rest of the way.
Martinez hit Long for a nine-yard score on Nebraska's next series before Corey Acosta nailed a 45-yard field goal a bit later in the quarter to make it a 21-17 game.
Martinez then went 4-of-5 for 77 yards on Nebraska's final drive of the half, a brisk five-play, 77-yard trek, which took just 34 seconds to complete.
Jamal Turner had a 36-yard catch before Osborne hauled in a 29-yard score and gave the Huskers a 28-17 halftime advantage.
Reed corralled an 18-yard score and Heard scampered in from 10 yards out in the third stanza, which extended the margin to 42-17.
Acosta split the uprights from 37 yards out in the fourth before Abdullah caught an 11-yard touchdown pass to conclude the scoring.
Earlier, Nebraska scored touchdowns on its first two possessions and took a 14-0 lead. Burkhead had a 57-yard TD scamper on Nebraska's opening series and Bell snagged a 26-yard reception for a score on its next trek.
Tracy Lampley returned Nebraska's ensuing kickoff 100 yards for a score to get Southern Miss on the board with 6:54 left in the first.
Nebraska, which has won every season opener since 1986, has won every game during the stretch by double digits ... Nebraska leads the all-time series between the teams, 3-1 ... The Huskers racked up 632 yards of total offense.