Lattimore redshirted his first year at Ohio State in 2014 and played in only seven games his redshirt freshman year in 2015, due to hamstring injuries. He fully recovered from the injuries to become a starter in 2016. On November 29, 2016, Lattimore was named First Team All-Big Ten by the coaches.
Coming out of Ohio State, Lattimore was projected to be a first round pick by the majority of NFL experts and analysts. He was invited to the NFL Combine, but chose not to perform the bench press, shuttle, and three-cone drill. He attended Ohio State's Pro Day and decided to only run positional drills for scouts and representatives. Although he had a history of hamstring injuries and was limited to a single year of starting experience in college, he was ranked the top cornerback prospect in the draft by NFLDraftScout.com, Sports Illustrated, ESPN, NFL analyst Bucky Brooks, and NFL analyst Mike Mayock. Lattimore was also ranked the fifth best cornerback by Pro Football Focus.
On June 3, 2017, the New Orleans Saints signed Lattimore to a fully guaranteed four-year, $15.35 million contract with a signing bonus of $9.31 million.
The Saints were expected to bring Lattimore along slowly and allow him to sit behind starters Delvin Breaux and P. J. Williams and compete for the role as the third cornerback on the depth chart against Ken Crawley and De'Vante Harris. Head coach Sean Payton named him the third cornerback behind P. J. Williams and Ken Crawley after Breaux suffered a fractured fibula on August 16, 2017. He started the first two regular season games after Crawley was listed as inactive for both.
He made his professional regular season debut on Monday Night Football during the Saints' season-opener against the Minnesota Vikings and recorded four solo tackles during the 29–19 loss. The following week, Lattimore made a season-high seven combined tackles, forced a fumble, and deflected two passes during a 36–20 loss against the New England Patriots. He left the game in the fourth quarter and was placed in concussion protocol after colliding with teammate Vonn Bell as they both tackled Brandin Cooks. Lattimore became the starting cornerback prior to Week 4 after Williams was demoted in relation with a disciplinary issue. On October 15, 2017, Lattimore recorded five combined tackles, deflected two passes, intercepted a pass attempt from Detroit Lions' quarterback Matthew Stafford, and returned it for a 27-yard touchdown during the 52–38 victory over the Lions. The interception and touchdown were the first of his career. On November 2, 2017, he was named the NFC Defensive Rookie of the Month. Lattimore missed Weeks 12–13 after suffering an ankle sprain during the Saints' Week 11 victory over the Washington Redskins. On December 21, 2017, it was announced that Lattimore was selected to play in the 2018 Pro Bowl. On December 24, 2017, Lattimore made five combined tackles, four pass deflections, and intercepted his fifth pass of the year off of Matt Ryan in the Saints' 23–13 victory over the Atlanta Falcons. Lattimore finished his rookie season with 52 combined tackles (43 solo), 18 pass deflections, five interceptions, and a touchdown in 13 games and 13 starts. His five interceptions were the fifth most of all players in 2017. Lattimore was named the NFL Defensive Rookie of the Year. Lattimore received an overall grade of 90.5 from Pro Football Focus and had the fourth highest grade among all cornerbacks in 2017. He was ranked 82nd by his peers on the NFL Top 100 Players of 2018, one of three rookies to make the list.
The Saints finished atop the NFC South with an 11–5 record. On January 7, 2018, Lattimore started his first NFL playoff game and recorded two solo tackles and a pass deflection during a 31–26 NFC Wild Card round victory over the Carolina Panthers. The following week, he made four solo tackles and deflected a pass in the Saints' 29–24 loss to the Minnesota Vikings in the NFC Divisional round, which became to be known as the Minneapolis Miracle.