The 29-year-old's normally potent changeup abandoned him, leaving the southpaw one-dimensional in a park where all weapons are needed.
"I really didn't have anything but a fastball," Vargas said. "It was kind of opposite from my last outing, where I really couldn't throw a changeup for a ball. And all of them tonight were balls. It was just one of those nights where I had to go out there and battle.
"My fastball was a fastball, but if I missed with it, they were doing damage, because they didn't have to worry about any other pitch. It was just a grind."
Vargas dug in and wound up allowing just those seven hits over six innings, but the five runs and two homers were both season highs, and three walks equaled his high there as well. Vargas is now 4-3 with a 3.28 ERA, with all three losses coming on the road.
While the Red Sox were teeing off early, the Mariners (16-21) didn't get the ball out of the infield in the first four innings against Lester, though Ichiro Suzuki finally reached base with two out in the fourth on an infield single off the left-hander's glove.
Lester, who grew up in Puyallup, Wash., and attended high school at Bellarmine Prep in Tacoma about 30 miles south of Seattle, finally gave up a pair of clean singles in the sixth to Michael Saunders and Dustin Ackley, but he escaped that one-out jam.
Jesus Montero and Justin Smoak then led off the seventh with base hits, but Lester again neutralized that rally when Seager lined into a double play to second baseman Dustin Pedroia. Alex Liddi followed with Seattle's third single of the frame, but Lester got Saunders to pop out and preserve the 5-0 lead.
Seattle finished with eight hits, but it was 0-for-6 with runners in scoring position. The Mariners are now 6-for-70 with runners in scoring position over their last 10 road games and are 1-9 in that span.
"Lester threw a good ballgame," said manager Eric Wedge. "We hit some balls hard for outs and a couple of our guys had some good at-bats tonight, but nothing with really any damage behind it. The hits they had were just the opposite of that. They got a couple home runs that inning for the three runs and that was the difference."
Boston indeed made better use of its nine hits, five of which went for extra bases. The Red Sox increased their Major League-leading doubles total to 103, including a pair of RBI rips by David Ortiz and Adrian Gonzalez in the first.
The Sox then played long ball in the fourth, with a two-run blast by left fielder Daniel Nava and a solo shot by catcher Kelly Shoppach. It was the first home runs of the season for both. Nava's only other Major League home run came in 2010 -- a grand slam on the first pitch of his big league career.
"I was more upset about that fourth inning than anything," said Vargas. "I had a chance to keep us in the ballgame even with mediocre stuff. I let the bottom part of their lineup get ahead of me and kind of put us out of the ballgame right there. I need to do a better job of keeping us right where we are, even though I don't feel my best."
Boston added its last run in the eighth on a bases-loaded sacrifice fly by Marlon Byrd off reliever Shawn Kelley.
Smoak went 2-for-4, and his double in the ninth was the Mariners' only extra-base hit. He's gone 8-for-16 over the last four games to lift his average 41 points to .214.
Ackley extended his hitting streak to 10 games with his sixth-inning single, while Ichiro collected two hits and moved into a tie with Joe Medwick for 98th on the all-time list with 2,471.