Wakefield (2-4) gave up four hits and one earned run over 7 1/3 innings to reach 2,777 innings with Boston, one more than Roger Clemens worked in a Red Sox uniform.
The 43-year-old left after yielding a pinch-double to Travis Hafner, who had been 0-for-10 against the knuckleballer.
Hideki Okajima and Ramon Ramirez each got one out, stranding pinch-runner Anderson Hernandez at third base to end the eighth. Daniel Bard worked the ninth for his second save in five chances.
Wakefield struck out six without a walk, continuing the Red Sox rotation's remarkable road run. Their starters are 9-0 with a 0.75 ERA in the last 10 games away from Fenway Park. The right-hander was 0-2 with a 13.97 ERA in his previous two starts but retired 15 in a row at one point and improved to 12-8 in his career against Cleveland.
The Red Sox have won 17 of 20 against Cleveland since trailing the Indians 3-1 in the 2007 AL championship series, then rallying to win the AL pennant and the World Series.
Boston is 8-2 and the Indians 3-7 in their last 10 games.
Cleveland took a 1-0 lead in the first. Shin-Soo Choo tripled with one out and scored when Jhonny Peralta's two-out grounder handcuffed third baseman Adrian Beltre for an error.
Boston got three unearned runs in the fourth off David Huff (2-7) after Victor Martinez reached when his two-out flyball was dropped by Trevor Crowe on the warning track in center for a two-base error.
Kevin Youkilis followed with a double off the scoreboard in left, scoring Martinez. Red Sox manager Terry Francona argued it was a home run and the umpires used instant replay, which showed the ball falling short by several feet.
David Ortiz drove home Youkilis with a single off the glove of second baseman Luis Valbuena. After Beltre singled, Bill Hall doubled in Ortiz for a 3-1 lead.
When Huff got Mike Cameron to pop to center, fans gave Crowe a mocking cheer as he made the ordinary play. But Crowe got a genuine ovation in the seventh after taking a hit away from Marco Scutaro with a diving catch.
Cameron robbed Crowe of extra bases in the sixth, snaring his drive with an over-the-shoulder catch on the warning track in center. Choo followed with a two-out single to become Cleveland's first baserunner since Beltre's error.
Shelley Duncan's home run off the left-field foul pole with two outs in the seventh pulled Cleveland to 3-2.
Huff gave up eight hits over six innings, walking one and striking out six. The left-hander fell to 1-7 in nine starts since April 21.
Boston OF Jacoby Ellsbury, limited to nine games this year by four broken ribs, will be checked by Dr. Lewis Yocum on Wednesday in Los Angeles. … Cleveland designated INF Mark Grudzielanek for assignment and Hernandez brought up from Triple-A Columbus. … Francona said RHP Jonathan Papelbon (bereavement list) worked out at Fenway Park. It's not known when Papelbon will return. … Boston OF J.D. Drew, batting .197 (13-for-66) against lefties, didn't start. He flied out as a pinch-hitter against RHP Chris Perez in the eighth.