Juan Nicasio was born in San Francisco de Macorís, Dominican Republic, and grew up in nearby Arenoso, where his father, Francisco, farmed coffee and rice. His mother is Aurelia Nicasio and he has one sister, Adria.
Nicasio signed with the Colorado Rockies at age 19. In 2006, he pitched for the DSL Rockies, going 2–1 with a 2.89 ERA in eight games (five starts). With the Casper Rockies in 2007, Nicasio went 0–3 with a 4.36 ERA in 13 games (eight starts) and in 2008, he pitched for the Tri-City Dust Devils and went 2–4 with a 4.50 ERA in 12 starts. With the Asheville Tourists in 2009, he went 9–3 with a 2.41 ERA in 18 starts, striking out 115 batters in 112 innings of work. He began the 2010 season with the Modesto Nuts.
On May 28, 2011, Nicasio was recalled from Double-A Tulsa to take Jorge de la Rosa's rotation spot. Bruce Billings was optioned to Triple-A Colorado Springs to make room. Nicasio made his debut that day, facing the St. Louis Cardinals, pitching seven innings while giving up one unearned run. The Rockies won 15–4, giving Nicasio his first major league win. His first major league strikeout was of Jaime García. In total, Nicasio gave up six hits, walked two, and struck out two. He made 13 starts that season with a 4–4 record and 4.14 ERA.
On August 5, 2011, while pitching in a game against the Washington Nationals, Nicasio was struck in the head by a line drive off the bat of Nationals shortstop Ian Desmond. Nicasio lost his balance and fractured a vertebra in his neck when he fell to the ground. During emergency surgery, doctors inserted pins into the fractured C-1 vertebra and secured a metal plate to the back of his neck. His recuperation was remarkably quick. Eleven days after the incident, he visited the dugout at Coors Field wearing a neck brace and came out on the field to a standing ovation. He continued to improve through physical therapy, and that winter he eased back into pitching in the Dominican Republic.
Nicasio returned to the mound for the Rockies in April 2012 and made a total of 11 appearances, with a 2–3 record and 5.28 ERA. On June 1, 2012, he injured his left knee while fielding a ground ball. After several attempts to drain the fluid in the knee failed, he underwent arthroscopic surgery in July and missed the remainder of the 2012 season. Nicasio came back in 2013 and made 31 starts, with a 9–9 record and 5.14 ERA. In 2014, he appeared in 33 games, but only 14 of them were starts. He had a 6–6 record and 5.38 ERA.
The Rockies designated Nicasio for assignment on November 20, 2014 and on November 24, 2014, he was traded to the Los Angeles Dodgers for a player to be named later or cash considerations. On December 16, minor league outfielder Noel Cuevas was sent to the Rockies to complete the trade.
Nicasio signed a one-year, $2.3 million contract with the Dodgers on January 16, 2015, to avoid salary arbitration.
Nicasio pitched out of the bullpen for the Dodgers during the 2015 season though he made a spot start in the first game of a doubleheader against the Rockies at Coors Field on June 2, giving up one earned run on three hits in two innings of work. In 53 appearances, he was 1–3 with a 3.86 ERA. The Dodgers chose not to offer him a contract after the season and he became a free agent.
On December 10, 2015, Nicasio signed a one-year, $3 million deal with the Pittsburgh Pirates. Following a stellar spring training that saw him strike out 24 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. On July 4, 2016, Nicasio became only the 74th player to pitch an immaculate inning in a Major League game.
Nicasio was claimed off waivers by the Philadelphia Phillies on August 31, 2017. The Phillies placed Nicasio on their Major League active roster on September 1, 2017.
On September 6, 2017, Nicasio was traded to the St. Louis Cardinals for infielder Eliézer Álvarez.