He played in Major League Baseball (MLB) for the Colorado Rockies, Los Angeles Dodgers, Pittsburgh Pirates, St. Louis Cardinals, Seattle Mariners, Philadelphia Phillies, and Texas Rangers.

[2] In 2008, he pitched for the Class A- Tri-City Dust Devils and went 2–4 with a 4.50 ERA in 12 starts, with 61 strikeouts in 54 innings.

[4] He played the 2010 season for the Class A+ Modesto Nuts, for whom he was the April 19, August 16, and September 6 California League Pitcher of the Week.

For the season he was 12-10 with a 3.91 ERA, with 171 strikeouts (leading the league, and tops in the Rockies organization) in 177.1 innings pitched.

[3][4] On May 28, 2011, Nicasio was recalled from Double-A Tulsa to take Jorge de la Rosa's rotation spot.

[6] Nicasio made his debut that day, facing the St. Louis Cardinals, pitching seven innings while giving up one unearned run.

[8] During emergency surgery, doctors inserted pins into the fractured C-1 vertebra and secured a metal plate to the back of his neck.

[8] He continued to improve through physical therapy, and that winter he eased back into pitching in the Dominican Republic.

[10] Nicasio returned to the mound for the Rockies in April 2012 and that season he made a total of 11 appearances, with a 2–3 record and 5.28 ERA, and 54 strikeouts in 58 innings.

After several attempts to drain the fluid in the knee failed, he underwent arthroscopic surgery in July and missed the remainder of the season.

[16] Nicasio signed a one-year, $2.3 million contract with the Dodgers on January 16, 2015, avoiding salary arbitration.

[22] Following a stellar 2016 spring training that saw him strike out 24 batters in 15 innings without conceding a run, as well as displaying excellent fastball velocity, Nicasio made the Pirates rotation to begin the year, beating out veteran Ryan Vogelsong.

[26] In aggregate in 2017, between the Pirates, Phillies, and Cardinals he led the NL in appearances with 76, as he was 5-5 with six saves, 21 holds (tied for 9th in the league), and a 2.61 ERA, and in 72.1 innings he gave up 20 walks and had 72 strikeouts.

[29] On December 3, 2018, the Mariners traded Nicasio, Jean Segura, and James Pazos to the Philadelphia Phillies for Carlos Santana and J. P.

In 2 appearances for the Rangers in 2020, Nicasio pitched to a horrific 40.50 ERA with only one strikeout, allowing 6 runs in 1.1 innings of work.