[2] Lexington won the state's Class 4A championship in 2013,[3] and Ciuffo was named the South Carolina Gatorade Player of the Year.

[1][5] However, he was also considered a likely first round pick in the 2013 Major League Baseball Draft, and said that the chances of his signing a contract and forgoing his college commitment are "50-50".

[12] In 2016, with the Charlotte Stone Crabs, Ciuffo compiled a .262 batting average with 15 RBI and 8 doubles in 59 games.

After the 2016 season, Ciuffo was named Tampa Bay's Minor League Defensive Player of the Year.

The Rays invited Ciuffo to spring training in 2018, but he was suspended for 50 games for his second positive test for a drug of abuse.

[22] He played in 12 games for the rookie–level Arizona League Reds and Triple–A Louisville Bats, and elected free agency following the season on November 4.

[29] Ciuffo went 1-for-5 with a double in two games for Baltimore, spending the majority of the year with the Triple-A Norfolk Tides, with whom he slashed .173/.241/.308.

[33] On June 7, 2023, Ciuffo announced his retirement from professional baseball, citing a broken foot that he suffered in spring training, which prevented him from playing for the Yankees organization.

His father, Tony, worked at the College of Charleston as its assistant director of athletics for media relations and the school's radio PBP announcer, which enabled Nick to observe the Charleston baseball team, and future major leaguers Brett Gardner and Michael Kohn.