Matsuzaka (5-0) won despite walking a career-worst eight batters in five innings, which also tied the major league high for walks this season. But he didn't allow a hit until Curtis Granderson's two-out RBI single in the fourth.
"There's not too many outings where you walk that many and still win," Boston manager Terry Francona said.
Matsuzaka had coldlike symptoms throughout the day and didn't feel good. Francona said he only planned to use him for five innings no matter what.
"He competes. He didn't have his best stuff or feel 100 percent physically," Francona added. "But tonight it was enough."
Craig Hansen, just recalled from the minors, gave up two runs in 1 2/3 innings. Hideki Okajima worked 1 1/3 scoreless innings before Jonathan Papelbon pitched the ninth for his 10th save in 10 chances.
Matsuzaka gave up one run and two hits with one strikeout, throwing 109 pitches.
"We couldn't get a hit bunched in with all the walks," Detroit manager Jim Leyland said. "We had good at-bats against Daisuke, but we couldn't get the big hit."
Tigers starter Jeremy Bonderman (2-3) allowed four runs and seven hits in six innings, walking two and striking out four.
"I think I threw the ball really well," Bonderman said. "The two home runs (Lowell and Youkilis) they hit were good pitches."
Lowell's two-run homer gave Boston a 2-0 lead in the second. The shot down the left-field line followed Manny Ramirez's leadoff double.
It was Lowell's first homer and RBI since last Sept. 29. He finished with three hits.
Lowell was sidelined from April 10-28 with a sprained left thumb. He led the team with 120 RBI last season and was the World Series MVP against Colorado.
"I think I'm getting to the point that I'm used to the tape job on my hand," Lowell said. "It feels like my right hand is so much stronger than my left hand gripping the bat, but tonight I saw the ball well."
Lowell has a book that comes out Tuesday and laughed off the suggestion that his big night was part of his publicity campaign.
Youkilis made it 4-0 with his two-run shot in the fourth after Lowell led off with a double. Youkilis hit a drive over the left-field fence for his fourth homer.
Ortiz made it 5-1 with a run-scoring single in the seventh and added his sixth homer in the ninth.
Pinch-hitter Marcus Thames had a two-run single with two outs in the seventh for Detroit.
- Francona said RHP Curt Schilling, on the 60-day disabled list with a tired shoulder, is scheduled to throw 25 pitches from 60 feet on Tuesday. If that goes well, he will begin a regular throwing program.
- The Tigers, now five games under .500, shook up a few things. Leyland promised a lineup overhaul after the team was swept in Minnesota. Detroit designated LF Jacque Jones for assignment and purchased the contract of outfielder Matt Joyce from Triple-A Toledo. Joyce was in the lineup in right field and hitting seventh, making his major league debut. He walked in his first big league plate appearance and finished 0-for-2. Taking Jones' place in left was usual DH Gary Sheffield. He asked to return to the outfield because he didn't feel comfortable as the DH. He caught Lowell's long drive to left against the wall in the seventh. Sheffield had been hitting third, but he batted sixth Monday night and went 0-for-1 with three walks. Carlos Guillen, who had been hitting sixth, went into the third spot. He was 1-for-3 with two walks.
- Hansen was recalled from Triple-A Pawtucket and Boston OF Brandon Moss was placed on the 15-day DL after having an appendectomy Saturday.