Held to just one run in the first two games of the series, the Red Sox collected 16 hits and posted their seconded-highest run output at home this season. It wasn't even close to enough to match the Cubs.
"I will say a number of positive things offensively, particularly the top half of the order," Boston manager John Farrell said. "Still not enough to come back from the deficit here tonight."
It started poorly right off the bat for starting pitcher Brandon Workman and the Red Sox. The right-hander gave up three runs in the first inning before retiring a batter.
"It was just inconsistency in being able to stay down in the zone and on an unforgiving night things got away from us," Farrell said.
Workman (1-2) allowed six runs and five hits in four innings.
"I just wasn't locating the fastball ball very well at all tonight," he said. "I walked a couple of guys in the first inning. I left some balls up over the plate they hit well. I just wasn't sharp tonight."
The Cubs jumped ahead 3-0 before making an out. Ruggiano homered off a billboard above the Green Monster seats after Chris Coghlan drew a leadoff walk. Anthony Rizzo walked, stole second and scored on Starlin Castro's single. Workman then struck out Luis Valbuena, bringing a loud mock cheer from the sweltering crowd.
Boston never came back.
Mookie Betts hit his first major league homer for the Red Sox, who lost for the ninth time in 13 games.
Red Sox DH David Ortiz became the 36th player in major league history to collect 1,000 extra-base hits with a ground-rule double.
Ruggiano drove in five runs, Darwin Barney had four hits and Nate Schierholtz added a solo homer for Chicago, which won for the sixth time in seven games away from Wrigley Field and posted its first interleague sweep of three or more games since taking three from Cleveland in 2009.
It was the Cubs' first interleague sweep on the road since winning three against the crosstown rival White Sox in 2007.
Boston had its streak of holding an opponent to three or fewer runs in 14 straight home games snapped, the longest single-season stretch since the 1917 White Sox did it in 20.
Unlike the first two games of the series when the teams combined for five runs and Boston was held hitless for 7 2-3 innings in the opener, there was plenty of offense to force both starting pitchers out early.
The teams combined for nine runs in the ninth inning — Chicago scored six — in a game that took 4 hours, 19 minutes.
Carlos Villanueva (4-5) allowed two runs in two innings of relief for the win.
Chicago starter Travis Wood lasted just 3 2-3, giving up three runs and seven hits.
Boston's Jonny Gomes had a sacrifice fly before Chicago built its lead to 6-1 in the fourth. Olt hit his two-run homer into Monster seats and Barney tripled and scored on Coghlan's sacrifice fly.
Ortiz had a sacrifice fly and Gomes an RBI single, slicing it to 6-3, but Castillo homered into the center-field bleachers off reliever Felix Doubront in the fifth.
Betts homered into the Monster seats. Schierholtz homered in the eighth when many of the sellout crowd had already left.
NOTES: Ortiz is the only active left-handed hitter with 1,000 extra-base hits. ... Farrell said OF Shane Victorino, on the 15-day DL since late May with a strained right hamstring, may take BP soon. He shagged fly balls in the outfield during BP, teaching rookie Betts how to handle the sun in right. ... Both teams are off Thursday. ... The Cubs are scheduled to open a three-game series at Washington on Friday at 11 a.m. when, in a statistical rarity at this point in the season, RHP Jason Hammel (7-5, 2.98 ERA) faces RHP Tanner Roark (7-5, 2.98). ... LHP Jon Lester (9-7, 2.92) is slated to go for the Red Sox against RHP Miguel Gonzalez (4-5, 4.56) when they open a three-game set against Baltimore.