The Steelers finished first in the AFC North with a 13–3 record and earned a first-round bye. On January 14, 2018, Smith-Schuster started in his first playoff game and made three receptions for five yards and a late touchdown in a narrow 45–42 loss to the Jacksonville Jaguars in the Divisional Round.
On January 18, 2018, the Pittsburgh Steelers promoted quarterback's coach Randy Fichtner to offensive coordinator after they opted not to renew former offensive coordinator Todd Haley's contract. Smith-Schuster entered training camp slated as a starting wide receiver after the Steelers traded Martavis Bryant to the Oakland Raiders for a third-round pick in the 2018 NFL Draft. Tomlin named Smith-Schuster a starting wide receiver to begin the regular season, alongside Antonio Brown.
Smith-Schuster started his second NFL season strong with nine receptions for 116 receiving yards in the 21–21 tie against the Cleveland Browns. He followed that performance up with a career-high 13 receptions for 121 receiving yards and a touchdown in a 42–37 loss to the Kansas City Chiefs. In Week 3, against the Tampa Bay Buccaneers, he recorded nine receptions for 116 yards in the 30–27 victory on Monday Night Football. Smith-Schuster broke another NFL record on November 25, 2018 against the Denver Broncos when he became to the first player ever to have two offensive touchdowns of at least 97 yards. The touchdown was part of a 13-reception, 189-yard performance in the loss. In Week 14 against the Oakland Raiders, Smith-Schuster caught 8 passes for 130 yards and 2 touchdowns in a 24–21 loss. During Week 16 against the New Orleans Saints, Smith-Schuster finished with 115 receiving yards as the Steelers lost 28–31; however, as the Steelers were progressing down the field into scoring position, Smith-Schuster committed a game-ending fumble. This would ultimately be one of the causes of the Steelers missing the playoffs that season, as wins by the Baltimore Ravens and Indianapolis Colts the following week officially eliminated them.
Smith-Schuster was voted team MVP by his teammates for the 2018 season, finishing the season with a team-high 111 receptions and 1,426 yards. He also had seven touchdowns on the season, finishing second on the team only to Antonio Brown's 15 touchdown catches. Smith-Schuster made his first career Pro Bowl in 2018 as an alternate, after teammate Antonio Brown announced that he would not participate in the game because of an injury. He received an overall grade of 81.8 from Pro Football Focus in 2018, which ranked as the 16th highest grade among all qualifying wide receivers.
Smith-Schuster has used Twitch to stream himself playing games including Fortnite and Call of Duty: WWII. In 2018 he participated in Ninja's record-breaking Fortnite stream including Drake and Travis Scott. While injured during the 2019 season, Smith-Schuster participated in a live Thursday Night Football stream with TimTheTatman, for which he was paid $100,000.
In February 2018, Smith-Schuster announced a partnership with the popular gaming group FaZe Clan to sell merchandise. He now has a YouTube channel using his full name that posts Call of Duty, Fortnite Battle Royale, and daily life videos that often feature his French bulldog Boujee.