The Red Sox handed the D-backs one of their most lopsided defeats of the year, as they beat the home team, 10-3, in front of 40,435, many of whom were rooting for Boston.
Arizona, which had won 12 of its last 14 games, also lost by seven runs on April 4 in Colorado.
"We didn't come out to play today," first baseman Conor Jackson said. "We've got to come out playing better against a team like that. Confidence-wise, we need to come out tomorrow and show that we can play with those guys."
One thing working in the D-backs' favor on Saturday is that Josh Beckett won't be able to start again. The right-hander kept Arizona's offense in check as he fanned eight in eight innings to raise his record to 9-0.
"He's got good stuff," Jackson said. "Probably one of the better pitchers we've seen all year. He had a great game. He was mixing his pitches well."
The D-backs' game plan was to jump on Beckett's fastball early in the count, but by the second time through the order, the right-hander had figured that out.
"Started us out with some breaking balls, whether it was curve or split and just had it rolling," manager Bob Melvin said of Beckett's adjustment the second time around. "Pitched in, pitched away, had real good stuff. When he's got good command, he's tough to deal with."
Things were not as good for Arizona starter Doug Davis, who struggled with his command throughout his four innings on the mound.
Julio Lugo led off the game with a homer to left, but things really fell apart for Davis (4-7) in the third when he walked Lugo and gave up a two-out single to Manny Ramirez. The lefty then left a cut fastball up and out over the plate that J.D. Drew deposited in the seats in left-center for a three-run homer and a 4-0 Boston advantage.
"[I] had a great plan to go after these guys, and not being able to execute gets frustrating out there," said Davis, who had pitched well in his three previous starts. "It was poor execution all night, falling behind hitters in 2-0, 2-1 counts and having to serve it up to them. And they know what's coming, because when I get behind in the count, obviously, I'm throwing a cutter."
The best example of Davis' command problems came in the third when he threw a pitch behind Lugo. Overall, he threw 46 strikes and 44 balls and walked five.
"I was pulling pitches," he said. "I mean, I pulled a cutter five feet on the other side of Lugo. Totally unintentional of course, I have nothing against him or the Red Sox. Just one of those days I couldn't even come close to where I wanted to throw it, and when I did, it felt like they were just teeing off."
Particularly Drew, who was a thorn in the D-backs' side when he was with the Dodgers, and used his first game at Chase Field this year to get his bat back on track. He hadn't homered in 33 games before his third-inning blast and he wasn't done for the night.
With his younger brother Stephen looking on at shortstop, Drew blasted his second three-run homer of the game in the sixth that put the game away for Boston.
The last time Drew hit two homers in a game was last August, also here at Chase Field, while the seven RBIs on the night set a career high for him.