He played college football for the USC Trojans and was selected by the Lions in the fourth round of the 2021 NFL draft.

[3] A five-star recruit ranked second among receiver prospects, St. Brown committed to the University of Southern California (USC) to play college football.

[13] On January 2, 2021, St. Brown announced on his Instagram account that he would be declaring for the 2021 NFL draft, and was projected by CBS Sports as a late first round pick.

[15] Other scouting reports, including ones by Pro Football Focus and The Draft Network, placed St. Brown anywhere from a third to fourth round selection, with emphasis on him being a second string receiver.

[23] St. Brown recorded his first career scoring play in a 2-point conversion attempt in their Week 6 loss of 34–11 against the Cincinnati Bengals.

[28] In their season opener against the Philadelphia Eagles, St. Brown put up an eight-reception, 64-yard performance with one receiving touchdown.

[32] In a Week 3 matchup against division rival Vikings, his streak would end when St. Brown received 6 passes for 73 yards with no touchdowns.

[33] This injury would cause St. Brown to miss their Week 4 matchup against the Seattle Seahawks, where the Lions would lose in a close 48–45 battle.

[34] Returning in Week 5 against the New England Patriots, St. Brown put up just 18 yards on four receptions, ending with the Lions getting shut out 29–0.

[46] In Week 11 against the Los Angeles Chargers, St. Brown caught eight passes for a career-high 156 yards and a touchdown in a 41–38 win.

[48] St. Brown finished the 2023 season third in the NFL with 1,515 receiving yards (behind Tyreek Hill and CeeDee Lamb)[49] He was selected as a First team All-Pro and earned Pro Bowl honors.

[50][51] In the Wild Card Round game against the Los Angeles Rams, St. Brown had eight receptions for 110 yards in his playoff debut, including a crucial first down pass from Jared Goff in the fourth quarter that secured a 24–23 victory, the Lions' first playoff win in over 30 years.

[57] In Week 4 of the 2024 season, St. Brown threw his first career touchdown pass on a trick play to Jared Goff in a win over the Seahawks.

[67] St. Brown is also a community ambassador for United Health Share Ministries, a Christian healthcare non-profit organization.