[6] As a senior, he enjoyed the best season of his career in 2012, leading the team with 112 tackles, including 7.0 for loss, a sack, and two interceptions, and was named second-team All-Pac-12.

[13] He made his professional regular season debut in the St. Louis Rams' season-opener against the Arizona Cardinals and recorded five combined tackles and a pass deflection in their 27–24 victory.

[14] On September 26, 2013, McDonald recorded three combined tackles before exiting the Rams' 35–11 loss to the San Francisco 49ers after slightly fracturing his right leg.

[14] On December 15, 2013, McDonald recorded five combined tackles, deflected a pass, and made his first career interception during a 27–16 victory at the New Orleans Saints in Week 15.

[14] He made his first career interception off a pass by Drew Brees that was originally intended for tight end Jimmy Graham on the Saints' first offensive play of the game.

[21] McDonald entered training camp slated as the starting strong safety after Darian Stewart departed during free agency.

Defensive coordinator Gregg Williams opted to move him to strong safety as McDonald was better suited for the position over Rodney McLeod.

[24] On December 7, 2014, McDonald made four tackles and intercepted a pass by Robert Griffin III in the Rams' 24–0 victory at the Washington Redskins in Week 14.

[24] In Week 16, he tied his season-high of 11 combined tackles (nine solo) and sacked quarterback Eli Manning during a 37–27 loss to the New York Giants.

[29] Head coach Jeff Fisher stated McDonald had been dealing with the injury throughout the entire season and was placed on injured reserve for his best interest of his sustained health for the future.

[31] In Week 3, McDonald recorded three solo tackles and sacked quarterback Jameis Winston during a 37–32 victory at the Tampa Bay Buccaneers.

[32] He finished his last season with the Rams with 64 combined tackles (50 solo), six pass deflections, a career-high two interceptions, and a sack in 16 games and 16 starts.

[11][39] In Week 10, he made his regular season debut as a member of the Dolphins and collected a season-high nine combined tackles in their 45–21 loss at the Carolina Panthers.

In the aftermath, McDonald was fined $390, received 36 months of probation, and was ordered to undergo 200 hours of community service in addition to attending a three-month alcohol program along with 18 narcotic anonymous classes.

[45] On March 29, 2017, while a free agent, McDonald was suspended for the first eight games of the 2017 season for violating the league's personal conduct policy, regarding his previous DUI charge.