Willis walked Nick Evans, the first Los Angeles Dodgers batter he faced to open the eighth inning in a spring-training game, and then came out after throwing one pitch to the next batter, Brian Barden.
The 2000 National League Rookie of the Year left the field with a trainer and was pointing to his left shoulder. The Cubs' medical staff will re-evaluate Willis.
"It's a mild setback, I guess," Willis said, according to USA Today. "Hopefully, it's nothing serious and I don't miss a lot of time. It's probably just fatigue. Hopefully just a couple of days and I'll get back on it.."
Willis, 31, had retired last July after going 0-3 with an 8.53 ERA in four games with triple-A Norfolk in the Baltimore' Orioles organization, but he signed a minor-league contract with the Cubs, his ninth team, in hopes of making a return to the major leagues.
Willis last pitched in the majors with the Cincinnati Reds in 2011. He has mostly struggled as a starter since the 2005 season with he posted a 22-10 record.