Seattle listed Darnold as questionable on the final injury report of the week due to an oblique issue.
"Really optimistic he's going to be able to play, and right now, we're going through all the protocols, one, just out of caution, to make sure we're ready to go," Macdonald told reporters during his final media availability before the game. "We'll test it out tomorrow to kind of make the final decision.
"But again, we're optimistic he's going to play, and if he doesn't, or at some point he doesn't, then Drew's (QB Drew Lock) ready to go, and that's why Drew's here. He's done a great job."
Darnold experienced discomfort early in Thursday's practice and stepped aside as a precaution. With Darnold sidelined, Drew Lock took the majority of the first-team practice snaps.
"In routes on air, just kind of felt a little something in my oblique," Darnold said. "Just didn't want to push it. It wasn't the day to push it. So, that was it. So, just came inside, got some rehab, and feel like I'll be ready to go for Saturday."
When asked about the chances of not playing against the 49ers, Darnold expressed strong confidence.
"Very low percentage," Darnold said. "Probably closer to zero."