Miguel Tejada added a two-run homer for Baltimore, which overcame a 4-1 deficit to avoid its fourth straight series sweep against the Red Sox.
Jim Johnson (1-1) allowed two runs in the bottom of the 10th, and had to leave with runners on first and second. Cla Meredith got the final two outs for his first save.
Kevin Youkilis had a double and two singles for the Red Sox, who went 4-6 on their 10-game homestand.
The Orioles loaded the bases with no outs against Scott Atchison (0-1) before Hughes, who struck out with two runners on in a 7-6 loss Saturday in his first major league game, singled to right. Wieters then grounded one up the middle and through a drawn-in infield, just past shortstop Marco Scutaro's diving bid.
J.D. Drew doubled in a run and scored on Bill Hall's single, but Boston's rally ran out of gas. Darnell McDonald fouled out and Scutaro hit a liner to second baseman Ty Wigginton to end the game.
Boston starter Tim Wakefield left with a runner on first and a 4-1 lead in the seventh, but Hideki Okajima gave up Nick Markakis' RBI double and Tejada's tying homer that caromed off the left-field foul pole.
With speculation that Wakefield will be taken out of the rotation when Daisuke Matsuzaka returns from the disabled list next weekend, the 43-year-old knuckleballer was charged with two runs and seven hits, and was saluted with a standing ovation when he left after 6 2/3 innings.
Manager Terry Francona hasn't identified which starter Matsuzaka will replace.
Unlike Wakefield's last start when the Texas Rangers set a club record with nine steals, the Orioles had just one.
Boston chased David Hernandez during its four-run sixth. Youkilis — Hernandez's last batter — tied it at 1 with a single to center. After hitting a long foul high off the Green Monster, David Ortiz, who entered with a .156 average, hit a tiebreaking RBI single off Mark Hendrickson.
Drew added a sacrifice fly and pinch-hitter Mike Lowell hit an RBI double off Jason Berken to make it 4-1.
Hernandez gave up three runs and four hits and five-plus innings.
The Orioles grabbed a 1-0 lead in the second on Craig Tatum's RBI single.
Boston third baseman Adrian Beltre had a very busy first inning. Nolan Reimold, the game's first batter, hit a grounder that bounced off his chest for what was initially called an error but was later changed to a hit. Beltre then booted a grounder from Adam Jones — the second batter — for an error before making a nice backhanded stab on Tejada's roller down the line, saving at least one run.
Beltre also made a good play on Tejada's hard grounder in the fifth. Tejada raised both arms in disbelief as he ran down the line.
Notes
Orioles RHP Koji Uehara, on the 15-day disabled list with a strained left hamstring, is scheduled to make a rehab start for Double-A Bowie on Tuesday. … Youkilis, trotting down the first-base line with his head down, collided with 1B Hughes on a pop-up in the second. The ball fell, but Youkilis was ruled out by plate umpire Jeff Kellogg for interference. … Matsuzaka, sidelined with a strained neck since spring training, is scheduled to throw a four-inning simulated game in Toronto on Monday, the last test before he's ready to return to the rotation.