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The Atlantic Coast Conference's leading passer was 30 of 43 with touchdowns covering 24 yards to Donovan Varner and 1 yard to Danny Parker in his third straight 300-yard performance for the Blue Devils (4-3, 2-1).
Duke never trailed, outgained Maryland 394-249, withstood the Terrapins' late charges and held on for the Blue Devils' third win in four games. They also claimed consecutive conference victories for the first time since 1994.
Chris Turner was 16-for-23 for 182 yards with a 67-yard touchdown to Davin Meggett for the Terrapins (2-6, 1-3), and he moved past Boomer Esiason into second place on the school's career passing list. But Turner couldn't keep Maryland from losing its third straight game and fifth in the last six.
Still, the Terrapins gave themselves some chances in the fourth quarter before the ACC's most turnover-prone team had problems keeping hold of the ball.
After forcing Lewis to fumble at the 2 and then forcing a punt with about 5 minutes left, the Terrapins gave it right back moments later when Turner's pass to Ronnie Tyler was intercepted by Vincent Rey. Maryland forced another punt with just under 2 minutes left, but Tony Logan fumbled it, Brandon King recovered and the Blue Devils ran out the clock.
Both teams kept the ball in the air despite rainy conditions.
Yet Duke seemed to have taken complete control with Lewis' second touchdown pass - a play-action flip to Parker that made it 17-6 with about 5 1/2 minutes left in the third and came after a 44-yard down-the-sideline heave to Connor Vernon.
The Terrapins responded moments later with their only touchdown of the day. Turner dumped off a swing pass to Meggett, and he cut back to the left, dashed down the sideline and ran through a tackler at the goal line to make it a four-point game.
For Duke, it was a rare matchup with an ACC rival it hadn't beaten in a decade, and an even rarer position - as a 4-point favorite. The expanded conference's rotating, divisional schedule kept Maryland off the Duke schedule since 2004.
With representatives of the Champs Sports and Chick-fil-A bowls looking on, Lewis picked up where he left off two weeks ago when he threw for a career-high 459 yards and five touchdowns in a 49-28 victory over North Carolina State.
Lewis regularly found receivers open across the middle, with his 24-yard pitch-and-catch to Donovan Varner making it 7-0 about 7 1/2 minutes in. Varner and Vernon - the ACC's only two players averaging at least 100 yards receiving - each hit that mark in this one, with Varner catching eight passes for 120 yards and Vernon finishing with five catches for 102 yards.
