On May 24, 2013, the 49ers signed McDonald to a four-year, $3.59 million rookie contract with $1.92 million guaranteed and a signing bonus of $997,584.

McDonald started the regular season as the second tight end on the depth chart, behind veteran Vernon Davis and ahead of Garrett Celek. In the 49ers’ season opener, he caught a 25-yard pass from Colin Kaepernick for his first career reception during a 28–34 victory over the Green Bay Packers. On September 22, 2013, he earned his first career start against the Indianapolis Colts and finished the loss with one catch for six receiving yards.

On September 14, 2014, McDonald started his first game of the season during a loss to the Chicago Bears and made his first catch of the season and only one of the game for 9 yards. He made his only other catch of the season during a Week 6 victory over the St. Louis Rams and finished the game with one reception for 21 receiving yards. On December 9, 2014, he was placed on season-ending injured reserve with a back injury.

He started his first and only season under new head coach Jim Tomsula as the backup to Davis once again. He started the season-opener against the Minnesota Vikings and made one reception for 5 yards during the victory. On November 22, 2015, McDonald caught his first NFL touchdown, a 19-yard pass from Blaine Gabbert against the Seattle Seahawks. The next game, McDonald made a season-high six catches for 71 receiving yards and a touchdown during a 19–13 loss to the Arizona Cardinals.

McDonald started his first season under head coach Chip Kelly as the starting tight end for the first time in his career, as Vernon Davis was traded midway through the previous season. In the 49ers’ season-opening victory over the Los Angeles Rams, McDonald caught two passes, one for 14 yards and an 8 yard touchdown from Blaine Gabbert. The next game, he caught a career-long 75-yard touchdown from Gabbert, during a 46–27 loss to the Carolina Panthers. On November 6, 2016, McDonald caught three passes for 85 yards and scored a 65-yard touchdown during a 41–23 loss to the New Orleans Saints. In a Week 12 matchup against the Miami Dolphins, he made four receptions for 60 yards during the 31–24 loss.

On December 9, 2016, the 49ers signed McDonald to a five-year, $35 million extension that included $16 million guaranteed and a signing bonus of $7 million. He was placed on injured reserve on December 12, 2016 after suffering a shoulder injury in Week 14 against the New York Jets.

On August 29, 2017, the 49ers traded McDonald and their 2018 fifth-round pick to the Pittsburgh Steelers in exchange for the Steelers’ 2018 fourth-round pick.

He received an overall grade of 70.2 from Pro Football Focus in 2018, which ranked as the 20th highest grade among all qualifying tight ends. Overall McDonald finished the year with 50 receptions for 610 yards and 4 touchdowns.