The left-hander, who underwent reconstructive elbow surgery in June 2006, gave up six runs and four hits with two walks in two-thirds of an inning.
While the outing wasn't what Estes had hoped for, it marked a big step forward after he spent all of 2007 rehabilitating his arm and pitching in the minor leagues.
Estes, who has 99 career wins and has won 15 games in three different seasons, said he wasn't nearly as pumped up for his first outing against major league hitters since April 5, 2006.
"I wasn't as geeked up as I thought I'd be," Estes said. "I was actually pretty cool, calm and collected today. Maybe I needed a little of that nervous energy, but I felt good physically and good going into it mentally."
Kansas City starting pitcher Gil Meche, likely to be the Royals' opening day starter, allowed two hits and struck out a hitter in two scoreless innings.
The right-hander, who was 9-13 with a 3.67 ERA in 2007 after signing a $55 million, five-year contract before last season, said he had trouble locating some pitches.
"I'm pleased with the cutter," Meche said. "Obviously the curveball and changeup weren't as sharp. But you get each (outing) under your belt and try to keep plugging away. I made good pitches but I made a bunch of bad ones as well."
Estes actually made several good pitches after allowing a leadoff walk to David DeJesus in the first inning. But Alberto Callaspo's grounder, a potential double play ball, got under Tony Clark's glove for a single. Another double-play ball by Alex Gordon drew a wide throw from Clark and helped open up the floodgates.
After Estes tired, he yielded a double to Justin Huber and a two-run homer to first baseman Ross Gload.
"I felt for the first 15 to 20 pitches my stuff was pretty good with the exception of the walk," Estes said. "I was kind of getting used to being on the mound. The last few hitters I felt my stuff wasn't quite as good and I left some balls up that got hit. ... It wasn't what I had in mind but needless to say I got my 30 pitches in."
Said Padres manager Bud Black: "His fastball had a little life. It was just one of those rough spring training outings."