Watson started 25 regular-season games this season, averaging 11.3 points. Tuesday night, he will make his first-ever postseason start, subbing for Rose.
The Chicago Bulls lead the best-of-seven Eastern Conference quarterfinals against the Philadelphia 76ers 1-0.
"I'm very comfortable," Watson said. "My teammates believe in me. Coach believes in me. That's all that really matters."
The Bulls went 18-9 during the regular season without Rose and 17-8 in games Watson started.
"Everyone has been playing their roles the whole season," Watson said. "Nothing is new. Just run the plays and play the defense like we've been playing.
"Everyone will go in with confidence, knowing they can make shots and play big minutes with Derrick out. We've been able to win games with Derrick out. It's nothing new for us."
Watson vowed to play aggressively.
"Just try to push the ball, make open shots, try to drive and get some assists," the mild-mannered guard said.