Barring an injury this spring, Wainwright will face the Pirates on Sunday, April 3 at Pittsburgh.
"I'd say it's pretty likely," Matheny said before Sunday's workout in Jupiter, Fla. "He's our guy. I mean, there's no doubt about it. We've got to see how the spring goes, any setbacks, any things that happen that takes us off our normal course. But this guy's the leader of our staff. He means so much to our club in a lot of regards. He leads well."
Wainwright, 34, missed most of the last five months of the 2015 season after tearing his left Achilles tendon while batting during a game on April 25 at Milwaukee.
Wainwright was 2-1 with a 1.61 ERA over just 28 innings in seven appearances last season. He came back late in the season to pitch in relief.
Wainwright was 20-9 with a 2.38 ERA in 32 starts in 2014 and 19-9 with a 2.94 ERA in 34 starts in 2013.
Wainwright, who missed the 2011 season after Tommy John surgery on his right elbow, will be making his fourth consecutive Opening Day start.
"It would be a great honor, for sure," Wainwright said. "It's something I've tried to get ready for and tried to prepare myself for for for a long time. I remember telling Tony (LaRussa) when he started (Chris Carpenter) one year, 'Next year, you're not going to have a choice in the matter. I'm going to make you start me Opening Day.' That pushed me. Now, it's just about competing, whether that's the first day or the fifth day."