Sale, out all season with a fracture in his right rib cage, allowed three hits with one walk and struck out five. The lefty reached 97 mph on his fastball during a 78-pitch, 53-strike outing.
"Step in the right direction," Sale said. "Command was spotty at times, but when I really had to bear down and get it, I felt like I was able to. I wish it ended up a bit different. But that's part of it."
The Red Sox are hoping the 33-year-old Sale can boost their chances of making the playoffs. This was just his 10th start for Boston since 2019.
"Just the overall strength towards the end of the game. I kinda felt better as it went on," Sale said. "Being able to have my best stuff, my powerful stuff, feeling strong in the fourth and fifth inning, is nice. I'll just keep building off that and we'll try to string together some wins."
Corey Kluber (5-5) allowed two runs and four hits in six innings to beat the Red Sox in consecutive starts. The right-hander went six shutout innings in a 7-1 victory at Boston last Wednesday.
Brooks Raley worked the ninth for his fifth save in six chances.
"Chris did a good job," Boston manager Alex Cora said. "And we didn't finish it."
Boston second baseman Trevor Story left the game when he was hit on the right hand by a pitch he swung at in the fifth inning.
Tampa Bay trailed 2-1 with two out in the sixth when Taylor Walls lined a single off Strahm's left wrist. The left-hander then threw wildly to first base, allowing Isaac Paredes to score. First baseman Franchy Cordero then threw off the mark to the plate, and Mejia scored the go-ahead run.
Alex Verdugo got Boston's first hit off Kluber when he flared a single to left with one out in the fifth. He went to third when Jeter Downs -- Story's replacement -- had a soft single to center. Boston took a 2-0 lead on Cordero's RBI sacrifice bunt and a run-scoring triple by Bobby Dalbec.
Boston All-Star Rafael Devers, who sat out the previous three games with lower back pain, went 1 for 4 as the designated hitter. Regular DH J.D. Martinez, added to the AL All-Star team Tuesday, got the night off.
Getting Sale's return in when they did means the Red Sox have the chance to start him again on Sunday vs. the New York Yankees, in Boston's final game before the All-Star break.
"The first one, just getting it out of the way," Sale said when asked about his most important takeaway from his season debut. "You never know what it's going to be. I just want to keep building off of it, keep throwing strikes, keep staying strong. Just attacking hitters, that's it."
"He threw the ball well, he finished well," the manager said. "Command of the pitches was OK, his delivery was under control, and he gave us five innings. So, that's a good start."
Being around his teammates and contributing his part felt OK to Sale, as well.
"It's everything to me," he said. "It means a lot."
The Associated Press contributed to this report.