Cavan Biggio also went deep for the Blue Jays and finished with three hits and three RBIs.
Ryu (2-1) struck out three and walked none. The left-hander permitted only one runner past second base and yielded just one extra-base hit to a team that came in ranked second in the majors with a .467 slugging percentage.
Rather than vie for strikeouts, Ryu said he was focused more on getting the Orioles to hit the ball weakly.
''I was able to keep them off balance,'' he said through an interpreter.
Signed in December to an $80 million, four-year contract, Ryu got off to a shaky start with Toronto in July before showing the form he displayed as a star with the Dodgers. He's given up a total of two runs in his last three starts after allowing eight runs over nine innings in his first two outings.
''That was vintage Ryu,'' Blue Jays manager Charlie Montoyo said. ''Ryu was outstanding. That's the reason we won the game.''
The two home runs were a factor, but mostly Ryu was the difference-maker.
''They didn't give Ryu that big contract for nothing,'' Orioles manager Brandon Hyde said. ''You just never know what he's going to throw. You don't know what side of the plate he's going to throw to. He's really tough on right-handers because he can locate it in. You saw a lot of us get jammed.''
The Blue Jays took control with a four-run third against Alex Cobb (1-2). Three infield hits produced a run before Grichuk delivered a three-run drive over the center-field wall. It was his third home run of the season, all in the last four games.
''Obviously, the pitch to Grichuk was middle middle and it was a poorly executed pitch,'' Cobb said. ''But most of the pitches that I had, I felt like I executed. I got the results.''
Cobb gave up five runs and eight hits in 6 2/3 innings. He's winless in his last four starts.
After hitting 31 homers last year, Grichuk was batting fifth, sixth or seventh in the order this season before Montoyo decided to move him into the No. 2 spot Sunday to replace injured Bo Bichette. Over the past two games, Grichuk has two homers, four hits and six RBIs.
Pedro Severino and Renato Nunez had RBIs for the Orioles, who have dropped two straight after winning seven of eight.
Blue Jays: Bichette (right knee sprain) had an MRI and will receive a second opinion on his injury, Montoyo said. Bichette leads Toronto with a .361 batting average.
Orioles: RH Dillon Tate (elbow contusion) came off the injured list and RH Evan Phillips was optioned to the team's alternate site.
Blue Jays: RH Nate Pearson (0-0, 5.11 ERA) makes his fourth start in his first big league season Tuesday night. Drafted 28th overall in 2017, the 23-year-old is looking to rebound after giving up four runs to Miami last week in 2 1/3 innings. ''I'm developing at the highest level,'' Pearson said Monday. ''When I don't have my best stuff, I'm going to struggle.''
Orioles: LH Wade LeBlanc (1-0, 7.13) has allowed a combined 10 runs over 12 innings in his last three starts.
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