Prior (1-0) made just one start in spring training and went on the disabled list due to right elbow inflammation. He got hit hard last week in a minor-league rehabilitation start but, backed by a quick 7-0 lead Wednesday, he allowed four hits, struck out six and walked one, throwing 92 pitches.
"I wanted to go out there and throw strikes," Prior said. "I had good down angle on the ball, throwing my fastballs down in the zone pretty good. I was happy with the command I did have on my fastball. Even the first three or four pitches of the game, I threw it right where I wanted."
Fans, some of whom booed Wood in the opener, cheered loudly for Prior, whose start was delayed a day by Tuesday's rainout.
"It was kind of a nice, little welcome back to the season," Prior said. "It was pretty cool."
Prior also started the four-run second with a single up the middle, scoring off Corey Patterson's RBI single. He added another single in the third inning.
While Cubs manager Dusty Baker said he was grateful for his offensive contributions, he was mostly glad to see Prior on the mound.
"You're always concerned when a guy hasn't pitched very much," Baker said. "He had good command, good tempo. His mechanics looked good."
Brian Lawrence (0-2) gave up seven runs and nine hits in 2 2/3 innings.
Lee hit a three-run homer in the first inning, and Chicago's runs in the second came on Patterson's RBI single, Lee's sacrifice fly, a run-scoring wild pitch and Jeromy Burnitz's run-scoring single.
"I hit it pretty good," Lee said of his homer. "The key to that was to keep it low because the wind was blowing in pretty hard."
Neifi Perez went 6-for-9 in the doubleheader, all singles. Perez started at second base in the first game and at shortstop in the second.
Prior said endurance was only a factor when he zipped around from first to third on Jerry Hairston's double in the third.
"I got a little winded out there running first to third," he said. "I haven't done that since college."
While Prior said he's not "100 percent" yet, that's news to the Padres.
"He threw very well," Padres manager Bruce Bochy said. "We didn't get much going off him. It didn't look like he was coming off rehab."
- Patterson has a nine-game hitting streak, the first for the Cubs at the start of the season since Brian McRae in 1996.