Garoppolo suffered a high ankle sprain during his team's Week 2 victory over the New York Jets. The 49ers initially believed the injury wasn't severe and left a small chance for him to play, but he was unable to practice this week.
Mullens will make his first start for the 49ers since 2018. The 25-year-old owns a 3-5 record over eight career starts. He's thrown 13 touchdown passes to 11 interceptions since entering the league.
Shanahan expressed confidence in Mullen's experience and ability earlier this week.
"Nick has got a lot of playing time with us, and 2018 prepared him for moments like this. He always does a good job in practice, and (we're) excited to see him get his opportunity," Shanahan said, according to ESPN's Nick Wagoner.
Shanahan also ruled out Tevin Coleman and Raheem Mostert for Sunday's action, according to The Sacramento Bee's Chris Biderman. The Niners bench boss later said George Kittle will miss the Week 3 contest as well, per NFL Network's Ian Rapoport.