He played in Major League Baseball (MLB) for the New York Mets, Washington Nationals, Chicago Cubs, and Colorado Rockies.

[2] Murphy attended Jacksonville University, where he played college baseball for the Dolphins under head coach Terry Alexander.

As a junior in 2006, Murphy posted a .398 batting average en route to being named the A-Sun Baseball Player of the Year.

[5] On August 2, a day after being promoted to the Triple-A New Orleans Zephyrs, the Mets left-handed reserve outfielder Marlon Anderson was placed on the disabled list, and Murphy was called up to the majors.

Later in the same game, he made a difficult catch against the left field wall, throwing out Hunter Pence at second base for a double play to end the inning.

Murphy hit his first home run in the bottom of the sixth inning against the Florida Marlins at Shea Stadium on August 9.

Although he is a natural third baseman, Murphy began to play left field in 2008, and continued in 2009, due to the presence of David Wright on the Mets.

[9] On March 30, 2010, Murphy hurt his knee in a spring training game against the St. Louis Cardinals in a rundown between third base and home plate.

[11] The following year, Murphy suffered a season-ending injury to his MCL on August 7, 2011 after a collision with the Atlanta Braves' José Constanza.

[13] Murphy was named as the Mets nominee for the 2012 MLBPAA Heart & Hustle Award, which was ultimately won by Mike Trout of the Angels.

[15] For the period ending September 1, Murphy was named the National League Player of the Week after accumulating five doubles, seven runs and thirteen hits.

Following the season, he was again nominated for the MLBPAA Heart & Hustle Award, this time losing out to Boston Red Sox second baseman Dustin Pedroia.

[19] In the deciding fifth game of the 2015 National League Division Series (NLDS) against the Los Angeles Dodgers, Murphy had three hits, including the game-winning home run in the sixth inning, to lead the Mets to a 3–2 win.

[21] Over the course of the NLDS and 2015 National League Championship Series (NLCS), Murphy became the first person in major league history to hit a home run in six consecutive postseason games, beating a record set by Carlos Beltrán, and became the second person, after Lou Gehrig, to have a hit, a run, and an RBI in seven consecutive postseason games.

[32] In 144 games, Murphy finished the year with a .322 batting average, 23 home runs, and 93 RBI, despite battling a knee injury for at least part of the season.

[34] On August 21, 2018, Murphy was traded to the Chicago Cubs in exchange for minor league infielder Andruw Monasterio and either a player to be named later or cash.

On October 28, 2020, Murphy was one of 147 players who were declared a free agent at the conclusion of the 2020 Major League Baseball season.

[39] On March 29, 2023, Murphy came out of retirement and signed with the Long Island Ducks of the Atlantic League of Professional Baseball.

[47] In 2011, Murphy appeared with fellow Major Leaguers Shane Victorino and Clay Buchholz on a special Veterans Day episode of the ABC series Extreme Makeover: Home Edition.

[49] When Daniel Murphy took a three-day leave of absence from the team to attend the birth of his child, something guaranteed by the MLB collective bargaining agreement, he received heavy criticism from New York City radio commentators Boomer Esiason and Craig Carton on their show for doing so.

While they were roundly criticized for their comments—including a statement by Mets manager Terry Collins where he told them to "look in the mirror"—Murphy himself said only that he was aware of the comments.

[17][52] In March 2015, Major League Ambassador for Inclusion, Billy Bean, visited the Mets spring training clubhouse.

Murphy, a devout Christian, made controversial comments[53][54] when he remarked on Bean, who is gay: "I do disagree with the fact that Billy is a homosexual.