2020
In week 8 against the Baltimore Ravens, Highsmith recorded his first career interception off a pass thrown by Lamar Jackson during the 28–24 win. In week 9 against the Dallas Cowboys, Highsmith recorded his first career sack on Garrett Gilbert during the 24–19 win. In week 13 against the Washington Football Team, Highsmith made his starting debut. In it, he recorded five tackles in the Steelers first loss of the season. Highsmith finished the remaining four games as the Steelers' starter, recording 23 more tackles as well as one sack that he recorded during their season finale against the Cleveland Browns.
2021
In week 17, against the Browns, Highsmith had two sacks in the 26–14 victory. In the 2021 season, he had six sacks, 74 total tackles (46 solo), and one forced fumble in 16 games and starts.
2022
In the regular season opener, Highsmith had three sacks and a forced fumble in the 23–20 overtime victory over the Cincinnati Bengals. In week 10, Highsmith had five tackles, two sacks, a tackle for loss and a forced fumble in a 20–10 win over the New Orleans Saints, earning American Football Conference (AFC) Defensive Player of the Week. He closed out the 2022 regular season with 2.5 sacks in a 28–14 win over the Browns.
He finished the 2022 season with 63 tackles, a team high 14.5 sacks, and league-leading five forced fumbles.
2023
On July 19, 2023, Highsmith signed a four-year, $68 million contract extension with the Steelers. The contract includes $27.74 million guaranteed and a signing bonus of $16 million. During week 2 of the 2023 season against the Browns, Highsmith intercepted the first pass from Browns quarterback Deshaun Watson and returned it 30 yards for his first NFL touchdown. He also recorded seven tackles and a forced fumble on Watson, which was recovered by Steelers teammate T. J. Watt for what eventually became the game-winning touchdown as the Steelers held on to win, 26–22. For his performance, Highsmith was named the AFC Defensive Player of the Week.