Juszczyk entered free agency for the first time in his career in 2017 and was the top fullback on the market. He received interest and offers from multiple teams, including the Philadelphia Eagles, Cleveland Browns, Buffalo Bills, and the San Francisco 49ers. The Philadelphia Eagles were the top team to possibly land the prized free agent at first, but the Buffalo Bills overtook them as the favorite, as they were looking for a stable replacement for Jerome Felton.
On March 9, 2017, the San Francisco 49ers signed Juszczyk to a four-year, $21 million contract that includes $7 million guaranteed and a signing bonus of $5 million. It was the largest contract for a fullback in NFL history.
In his 49ers debut, Juszczyk had two receptions for 17 yards in the season-opening 23–3 loss to the Carolina Panthers. On December 19, 2017, he was named to his second Pro Bowl.