As a high school baseball player, Nieuwenhuis was a lightly recruited second baseman and pitcher whose fastball reached 90 miles per hour. Nieuwenhuis played three seasons of baseball at Azusa Pacific University in Azusa, California. There he led the Cougars to back-to-back NAIA World Series appearances in 2007 and 2008 and set school career records in runs scored, with 190, and triples, with 12.

Nieuwenhuis was drafted by the New York Mets in the third round of the 2008 Major League Baseball draft out of the Azusa Pacific University. In the minors, Nieuwenhuis primarily was a center fielder, and after hitting .298 in Triple-A Buffalo, Nieuwenhuis was added to the Mets 40 man roster on November 18, 2011. After performing well during his debut with the Mets, Nieuwenhuis garnered the moniker “Captain Kirk” from Mets fans, in reference to the fictional Captain Kirk from the 1960s television series Star Trek.

Nieuwenhuis began his professional career with the Brooklyn Cyclones in the New York–Penn League, where he played 74 games and hit .277. Nieuwenhuis had 15 doubles, five triples and three home runs among 79 hits in 319 plate appearances. Following his first professional season, Nieuwenhuis continued to play well throughout the Mets’ Minor League system. He played at every level, finishing the 2010 campaign at Triple-A Buffalo. In 2011, Nieuwenhuis was shut down with a torn labrum in his non-throwing shoulder. It cost him most of the second half of his season.

Nieuwenhuis was called up by the Mets on April 7, 2012, to replace the injured Andrés Torres. Nieuwenhuis got his first major league hit, an infield single, on the same day he was called up; Nieuwenhuis finished the day 2-4. On April 9, in only his second start and third major league game, Nieuwenhuis hit his first Major League home run against Nationals pitcher Edwin Jackson. On April 27, he hit a walk-off single against the Miami Marlins off of Marlins closer Heath Bell giving the Mets the series sweep against the Marlins.

On June 10, 2013, Nieuwenhuis was again called up to the Mets playing center field.

Nieuwenhuis played in 61 games with the Mets in 2014. Over 112 at-bats he hit .259 with an .828 OPS and three home runs.

Nieuwenhuis was designated for assignment on May 19, 2015.

Nieuwenhuis was traded to the Los Angeles Angels of Anaheim for cash considerations on May 27, 2015. He was designated for assignment on June 10.

Nieuwenhuis was claimed by the New York Mets 17 days after the Mets traded him to the Los Angeles Angels of Anaheim. Nieuwenhuis was sent to the Las Vegas 51s and was later promoted back to the New York Mets on July 6, 2015.

On July 12, 2015, he hit three home runs in a game against the Arizona Diamondbacks. He was the first player to accomplish this at Citi Field. He is the tenth player in franchise history to hit three home runs in one game and the first to do so in a Mets’ home game. When interviewed after his exceptional game that day, Kirk commented in response to his critics: “there’s more to life than baseball”. On July 29, Lucas Duda joined Nieuwenhuis as the second Met to accomplish the feat at home.

On September 8, 2015, Nieuwenhuis hit a pinch-hit, go-ahead home run off Jonathan Papelbon of the Nationals, breaking an eighth inning tie and handing the Mets an 8-7 win, a game in which the Mets had once trailed 7-1. After their third consecutive comeback win the next day, the Mets swept the Nats, moving themselves to 7.0 games ahead in the NL East.

On December 23, 2015, Nieuwenhuis was claimed by the Milwaukee Brewers off of waivers. Nieuwenhuis was one of nine players competing to be the Brewers center fielder for the 2016 season. On December 3, 2016, Nieuwenhuis and the Brewers agreed to a one-year, $900,000 contract for the 2017 season. He was designated for assignment on April 21, 2017.

On November 14, 2017, Nieuwenhuis signed a minor league contract with the Seattle Mariners. He was assigned to AAA Tacoma Rainiers for the 2018 season. Nieuwenhuis was released by the organization on August 2, 2018.

On March 19, 2019, Nieuwenhuis signed with the Long Island Ducks of the independent Atlantic League of Professional Baseball.

On July 12, 2019, Nieuwenhuis retired from baseball.