McDonald was selected by the San Francisco 49ers in the second round of the 2013 NFL draft, and spent four seasons with the team.

He also competed in basketball and was a standout athlete for the East Chambers High School track team.

[14] 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.

[15] 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.

[18] 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.

[22] On November 22, 2015, McDonald caught his first NFL touchdown, a 19-yard pass from Blaine Gabbert against the Seattle Seahawks.

[23] McDonald finished the 2015 season with 30 receptions, 326 receiving yards, and three touchdowns while appearing in 14 games and 11 starts.

[25][26] 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.

[39] During Monday Night Football against the Tampa Bay Buccaneers in Week 3, McDonald finished with a career-high 112 receiving yards, including a 75-yard touchdown, as the Steelers won 30–27.

[43] In week 2 against the Seattle Seahawks, McDonald caught seven passes for 38 yards and two touchdowns as the Steelers lost 26–28.