The win lifted Creighton to 9-3 overall and 1-0 in the MVC, Southern Illinois fell to 3-9 on the season and 0-1 in the MVC.
Trailing 19-17 midway through the opening period, the Bluejays got going from beyond the arc to bolt out on a 9-0 run in under a minute. Junior Jordan Garrison gave Creighton a 20-19 lead with 7:22 on the clock to start the run, then junior Sarah Nelson converting a running layup into a traditional three-point play. Freshman Marissa Janning capped the run with a trifecta from the right wing to give the Jays a 26-19 edge with 6:24 remaining.
Creighton pushed its lead to 12 by the break as junior Carli Tritz was fouled on a desperation three in the closing seconds. Tritz hit two of three to make it 41-29 at half.
The Bluejays opened the second period with a quick 7-0 run to push their lead to 19 points at 45-29 on a bucket by Nelson, one from junior Alyssa Kamphaus and a three-ball from senior Ally Jensen.
Southern Illinois responded with a 7-1 burst to pull within 13 at 49-36, but the Jays slammed the door on the game with an 8-2 run to push their lead back to 19 at 57-38 with 13:23 left.
Nelson led all scorers with 18 points, while Janning finished with 14, Garrison had 12 and Kamphaus reached double-figures for just the fourth time with 10 points.
Rishonda Napier came off the bench to lead Southern Illinois with 16 points.
The victory gave Creighton ten consecutive wins over Southern Illinois and moved head coach Jim Flanery to 8-3 in MVC openers.
The Jays continue their MVC opening road trip at Evansville on Saturday, Jan. 5 at 5 p.m.