Lewis completed 17-of-28 passes for 141 yards with touchdowns covering 7 and 20 yards to Riley for the Blue Devils, who shook off a pregame weather delay and scored on four straight possessions to secure their first season-opening victory since beating East Carolina in 2002.
Clifford Harris added two 1-yard scoring runs for Duke, which snapped a nine-game losing streak with its most lopsided victory since a 40-14 rout of VMI in 2005. The Blue Devils had lost 31 of the 32 games that followed that victory.
Rodney Landers rushed for 96 yards and had a nifty 47-yard touchdown run for the Championship Subdivision's Dukes (0-1). But he was just 4-of-9 passing for 51 yards, and allowed Duke to take control by turning it over on James Madison's first two possessions of the second half.
First, he fluttered a pass deep in Duke territory and it was intercepted by Jabari Marshall, whose 67-yard return to the Dukes' 22 set up Harris' second touchdown six plays later that put the Blue Devils up 21-7.
Landers then opened the Dukes' next drive by fumbling away a keeper, Greg Akinbiyi recovered at the 34 and six plays later Lewis found Riley in the end zone from 20 yards out to give Duke a three-touchdown lead.
Lewis put the Blue Devils ahead to stay with 5 seconds before halftime, hitting Riley with a 7-yard scoring pass to make it 14-7.
Riley finished with seven catches for 67 yards to help Cutcliffe become the first coach to win his Duke debut since Fred Goldsmith opened the 1994 season with a victory over Maryland.
Even Duke's historically horrendous special teams got into the scoring act. Nick Maggio kicked a 27-yard field goal for the Blue Devils, whose kickers were a combined 3-of-11 on field-goal attempts during the 1-11 season that cost Ted Roof his job.
Nearly everything clicked for Duke under Cutcliffe, the former Mississippi coach whose December hiring reinvigorated a laughingstock program that had lingered at the bottom of the bowl subdivision for nearly two decades.
The start of the Cutcliffe era was delayed 1 hour, 27 minutes by lightning, but Duke's offensive performance wound up being worth the wait.
Harris' first touchdown run came on Duke's second possession, was set up by a pretty 14-yard scramble by Lewis and capped an 11-play, 66-yard drive. But the Dukes tied it right away on Landers' long scoring run, with the dual-threat quarterback -- called "the Tim Tebow of I-AA" by Cutcliffe -- taking off right on a keeper, then cutting back left through the Blue Devils' defense to make it 7-all.