After Padres manager Bud Black was ejected by plate umpire James Hoye in the second after Lester's first pitch to Middlebrooks was called a strike.
Black yelled from the dugout and was ejected.
Black walked on the field and talked to Hoye and crew chief John Hirschbeck before heading to the clubhouse.
On the next pitch, Middlebrooks tied the game at 2-2 with a long homer, his third of the season.
"I was looking for a cutter in. That's his pitch. He threw it and left it over the plate," Middlebrooks said. "I've played behind him a lot. I know what he likes to do."
Middlebrooks and Lester played in Boston together from 2012-14.
"I don't like to say it was one pitch that did me in, but I just didn't execute the cutter in to Middlebrooks," Lester said. "He made me pay for it, especially after we scored two off of Cashner."
Black didn't even make it back into the clubhouse in time to see Middlebrooks' homer.
"Will got us back on the board with a big swing," Black said. "From there Cash held it together and the bullpen did a nice job."
Lester (0-2), who signed a $155 million, six-year contract as a free agent, has a 6.89 ERA after three starts.
"I don't like to evaluate things that way as far as being almost there or not almost there, but it was better," Lester said.
"For the most part, I did a pretty good job of keeping the ball on the ground and that's important, it means I'm getting action on the pitches I need, getting some mishits, which was good today."
Lester gave up three runs and six hits in 5 1-3 innings. He alertly tossed his glove — with the ball stuck in the webbing — to first baseman Anthony Rizzo for an out after fielding Clint Barmes' comebacker in the second.
Joaquin Benoit pitched a scoreless ninth for his first save. Padres closer Craig Kimbrel got the day off after pitching the previous two days.
Kris Bryant, who made his major league debut on Friday, doubled and was hit by a pitch in going 1 for 3. He is 3 for 10 with one RBI in three games for the Cubs.
"I think today I finally settled down after the first, second inning and really started to make pitches," Cashner said.
"For the most part the sinker was down. Really good change-ups today and some really good sliders."
Lester was pulled after 97 pitches in the sixth with runners on first and second and one out. Reliever Brian Schlitter retired the first batter he faced, but gave up a go-ahead single to Will Venable.
Cubs manager Joe Maddon doesn't expect to see the early season struggles continue for Lester, who experienced "dead arm" issues in spring training.
"He is getting better," Maddon said. "I think he is getting a little bit sharper with everything. You can see he was frustrated on certain pitches today, but like I said, I think this one (start) or the next one I think you're going to see him getting back to normal."
Solarte homered off Jason Motte in the seventh.
The Cubs took advantage of two errors by the Padres to score twice in the first.
Black had a mound visit in the first inning after the two errors, but the message wasn't solely directed at Cashner.
"I had a few things to say to the guys," Black said. "I'd rather not share exactly what I said. I think it was the time for me to get the group together."
Padres: Odrisamer Despaigne (1-0) will try to back up an impressive start against the Diamondbacks with his second start of the season at Colorado on Monday.
Cubs: Jake Arrieta will be making his first start on the road against Pittsburgh on Monday. In two starts, the right-hander is 1-1 with a 1.98 ERA.
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