Youkillis drilled his third spring homer with a man on in the first, and doubled home a run in the second. Both blows came off Pirates starter Phil Irwin (0-1).
Irwin walked the first two men he faced in the third. Mike Zagurski relieved him with one out and also walked Dan Johnson to load the green-colored bases for Mesa, who unloaded them with a shot into the left-center bleachers.
The Pirates (9-13) broke through in the fourth on RBI doubles by Pedro Alvarez and Gaby Sanchez, with Travis Snider adding a sacrifice fly later in the inning to make it 8-3.
Alvarez went 2-for-2, with two doubles and a walk to raise his spring average to .172.
Clint Barmes added a solo homer, his second, in the fifth.
Up next: James McDonald hopes for a carryover from his last start -- he retired 14 of the last 17 Blue Jays he faced on Wednesday -- when he faces the Red Sox at McKechnie Field on Monday at 1:05 p.m. ET.