It was Farrell's 10th overturned call in 16 challenges. An inning later, Lester allowed three straight hits to Brett Gardner, Derek Jeter and Jacoby Ellsbury.
But just as replay helped the Red Sox escape the fifth, it also nixed their offensive hopes in the sixth inning.
Dustin Pedroia led off with a line drive into the left-center-field gap and decided to test Ellsbury's arm. Sliding headfirst into second, Pedroia wind-milled his arm around a Brian Roberts tag and was initially ruled safe.
That prompted Yankees manager Joe Girardi to jog out and use his own challenge. After another short umpire conference with the headsets, Pedroia was called out. The Red Sox proceeded to go down in order.
"We're all for it. That's what we preach to guys," Farrell said of Pedroia's hustle. "If they get thrown out on a smart aggressive play, he gets a pat on the back. Jacoby makes an on-line throw, it's a bang-bang play, but we'll take that opportunity every time it's offered to us."
Both challenges lasted under one minute before play resumed.
Jake Kring-Schreifels is an associate reporter for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.