Flacco shrugged off concerns about having missed the entire preseason schedule and most of training camp with a back injury, and was effective against a Bengals defense that has been tough on him over the years. He was 9 of 17 with an interception.
Baltimore's defense made things rough for Bengals quarterback Andy Dalton, who went 16 of 31 for 170 yards and tied a career-high with four interceptions. He also lost a fumble.
It was the fourth-worst loss for Cincinnati in a regular-season opener. The Bengals also were shut out in an opener for the first time since 1979.
Flacco completed his first five pass attempts on the Ravens' first possession as they drove 57 yards in 14 plays including a 25-yard field goal by Justin Tucker to put them ahead 3-0.
Joe Mixon made his NFL debut on the Bengals' second series with 19 yards on three carries and one reception. But the promising drive stalled when Ravens linebacker Patrick Onwuasor tipped a Dalton pass into the arms of cornerback Brandon Carr for his 16th career interception, but only his second since 2013.
Ravens linebacker C.J. Mosley's interception in the end zone stalled another long Cincinnati drive.
After Flacco was sacked by defensive tackle Geno Atkins in the second quarter to force a punt, the Bengals couldn't cash in.
With 1:52 left in the half, Flacco hit wide receiver Jeremy Maclin on a quick slant resulting in a 48-yard touchdown putting Baltimore ahead 10-0.
Maclin had two catches for 56 yards.
Dalton's third interception was disastrous for Cincinnati as Terrell Suggs tipped a pass high in the air and into Lardarius Webb's hands at the 2-yard line. Terrance West's touchdown run made the halftime score 17-0.
West rushed for 19 carries for 80 yards and a score.
Bengals linebacker Nick Vigil began the second half by intercepting Flacco's pass at the Ravens 26-yard line.
However, the Ravens' defense came up with another big play when linebacker Terrell Suggs swatted the ball out of Dalton's hand for a fumble that was recovered by Baltimore at the 12. Suggs had two sacks.
Pass interference and holding penalties extended an 18-play, nine-minute, 38-second drive for the Ravens. Tucker converted from 25 yards out to make the score 20-0 late in the third quarter.
NOTES: Bengals RG Trey Hopkins, one of three new starters on the offensive line, suffered a left knee injury in the second quarter and did not return. T.J. Johnson replaced him. ... Baltimore, coming off an injury-riddled offseason, lost two key players when linebacker Za'Darius Smith (knee sprain) and running back Danny Woodhead (hamstring) left with injuries in the first half. ... Bengals first-round draft choice WR John Ross was inactive due to a knee sprain. ... Bengals LB Vontaze Burfict and CB Adam Jones were suspended for Sunday's game. ... Baltimore now leads the all-time series 22-21. Cincinnati has won six of the past eight meetings, but Sunday's loss snapped a five-game winning streak over the Ravens at Paul Brown Stadium.