2013

On June 14, 2013, the St. Louis Rams signed McDonald to a four-year, $3.79 million contract that includes a signing bonus of $679,740.^[11] McDonald entered training camp slated as the starting free safety.^[12] Head coach Jeff Fisher named him the starting free safety to start the regular season, alongside strong safety Darian Stewart.^[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.^[15] On September 27, 2013, the St. Louis Rams placed McDonald on injured reserve with a designation to return list.^[16] The injury sidelined him for six games (Weeks 5–10) and he would return to practice on November 21, 2013. He returned in Week 12 and made six combined tackles during a 42–22 win against the Chicago Bears.^[17][18] In Week 14, he collected a season-high eight combined tackles in the Rams' 30–10 loss at the Arizona Cardinals.^[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.^[19] The following week, McDonald recorded six solo tackles and made his first career sack on quarterback Mike Glennon during a 23–13 win against the Tampa Bay Buccaneers in Week 16.^[20] McDonald finished his rookie season in 2013 with 53 combined tackles (45 solo), four pass deflections, a sack, and an interception in ten games and ten starts.^[21]

2014

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.^[22] Head coach Jeff Fisher officially named McLeod and McDonald the starting safeties to begin the season.^[23]

In Week 5, he collected a season-high 11 combined tackles (ten solo) and broke up a pass during a 34–28 loss at the Philadelphia Eagles.^[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.^[24] He finished his second season with a career-high 105 combined tackles (84 solo), six pass deflections, two sacks, and an interception in 16 games and 16 starts.^[21]

2015

McDonald and McLeod entered training camp slated as the starting safeties.^[25] Head coach Jeff Fisher officially named them the starting duo to begin the season.^[26]

On September 27, 2015, McDonald collected a season-high eight combined tackles in the Rams' 12–6 loss to the Pittsburgh Steelers in Week 3. The following week, he recorded six combined tackles and a sack during a 24–22 win at the Arizona Cardinals in Week 4.^[27] He was inactive during the Rams' Week 9 loss at the Minnesota Vikings after injuring his foot the previous week.^[28] On December 9, 2015, the St. Louis Rams placed McDonald on injured reserve due to a shoulder injury that would require surgery.^[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.^[30] He finished the 2015 season with 63 combined tackles (39 solo), a pass deflection, and a sack in 11 games and 11 starts.^[21]

2016

The St. Louis Rams moved back to Los Angeles in 2016 after 21 seasons in St. Louis. Head coach Jeff Fisher retained McDonald as the starting strong safety to begin the regular season, along with free safety Maurice Alexander.^[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] The following week, he made one tackle, two pass deflections, and intercepted a pass by Carson Palmer during a 17–13 victory at the Arizona Cardinals in Week 4.^[32] On November 27, 2016, McDonald recorded a season-high seven solo tackles during a 49–21 loss at the New Orleans Saints in Week 12.^[32] On December 12, 2016, Los Angeles Rams' general manager Les Snead fired head coach Jeff Fisher and named special teams coordinator John Fassel the interim head coach for the last three games of the regular season. The Rams stood at 4–9 at the time and suffered a 42–14 home loss to the Atlanta Falcons the previous day.^[33] On January 1, 2017, he made five combined tackles, broke up a pass, and made an interception during the Rams' 44–6 loss to the Arizona Cardinals in Week 17.^[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.^[21] He earned the 58th highest overall grade from Pro Football Focus, among the 89 qualifying safeties.^[34]

2017

On March 29, 2017, it was reported that McDonald received an eight-game suspension for violating the league's substance abuse policy. The suspension was in relation to his arrest the previous year (see personal life).^[35] He also attended a meeting with the Miami Dolphins on the same day he received his suspension.^[36]