On July 6, 2010, McDonagh signed an entry-level contract with the Rangers, forgoing his senior season at Wisconsin and joining childhood friend and former Wisconsin teammate Derek Stepan in New York.

After beginning the 2010–11 season with the Rangers' American Hockey League (AHL) affiliate, the Hartford Wolf Pack, he was promoted to the Rangers on January 3, 2011.
He played his first career NHL game on January 7, 2011, against the Dallas Stars.
He then earned his first NHL point on an assist of a Brandon Prust goal against the Carolina Hurricanes on January 20.
On March 20, McDonagh was the victim of an elbow to the head from Pittsburgh Penguins forward Matt Cooke, who was subsequently suspended for the remainder of the regular season and the first round of the 2011 Stanley Cup playoffs.

On April 9, 2011, McDonagh scored the game-winning goal, the first of his career, against the New Jersey Devils, earning the Rangers the eighth and final playoff spot in the Eastern Conference.

As a result of the 2012–13 NHL lockout, McDonagh signed a contract with Barys Astana of the Kontinental Hockey League (KHL).
He became the first American NHL player to join the KHL as a result of the lockout.

On July 8, 2013, McDonagh signed a new six-year, $28.2 million contract with New York.
He led all Rangers defensemen with 43 points in the 2013–14 season as the Rangers finished fifth in the Eastern Conference.
The team defeated the Philadelphia Flyers, Pittsburgh Penguins and Montreal Canadiens en route to the 2014 Stanley Cup Final against the Los Angeles Kings, where the Rangers lost the series 4–1.
During the playoffs, McDonagh was tied for the lead amongst defensemen in assists (13) and ranked second in points (17).
For his season's efforts, McDonagh was named Rangers' MVP and the recipient of the Players' Player Award, given to the Ranger "who best exemplifies what it means to be a team player".
He became just the second Rangers defenseman to hold both awards after Brian Leetch did so in the 2002–03 season.

On October 6, 2014, McDonagh was named the 27th captain in Rangers history, filling the vacancy left by Ryan Callahan the previous season.
Martin St. Louis, Marc Staal, Dan Girardi and Derek Stepan were named his alternates.
McDonagh became the fourth-youngest Ranger captain and 11th defenseman to hold the honor.
In his first season as captain, he led his team to the Presidents' Trophy and were ultimately eliminated in the Eastern Conference Finals by the Tampa Bay Lightning in seven games.
On May 30, 2015, it was revealed that McDonagh had played the final three games of the series with a broken foot.

McDonagh continued his strong play and leadership into the 2015–16 season, his second as team captain.
However, during a February 6, 2016, game against the Philadelphia Flyers, McDonagh suffered a concussion after getting punched by Flyers' forward Wayne Simmonds after McDonagh cross-checked Simmonds.
McDonagh missed eight games as a result, including a February 14 rematch between the two teams, during which Rangers' rookie defenseman Dylan McIlrath fought Simmonds.
Still feeling the effects of the concussion, McDonagh was scratched for two games of the Rangers first round playoff series against the Pittsburgh Penguins, which the Rangers ultimately lost in five games as the Penguins eventually went on to win the Stanley Cup.
On July 6, 2010, McDonagh signed an entry-level contract with the Rangers, forgoing his senior season at Wisconsin and joining childhood friend and former Wisconsin teammate Derek Stepan in New York. 
After beginning the 2010–11 season with the Rangers' American Hockey League (AHL) affiliate, the Hartford Wolf Pack, he was promoted to the Rangers on January 3, 2011. He played his first career NHL game on January 7, 2011, against the Dallas Stars. He then earned his first NHL point on an assist of a Brandon Prust goal against the Carolina Hurricanes on January 20. On March 20, McDonagh was the victim of an elbow to the head from Pittsburgh Penguins forward Matt Cooke, who was subsequently suspended for the remainder of the regular season and the first round of the 2011 Stanley Cup playoffs.
On April 9, 2011, McDonagh scored the game-winning goal, the first of his career, against the New Jersey Devils, earning the Rangers the eighth and final playoff spot in the Eastern Conference.
As a result of the 2012–13 NHL lockout, McDonagh signed a contract with Barys Astana of the Kontinental Hockey League (KHL). He became the first American NHL player to join the KHL as a result of the lockout.
On July 8, 2013, McDonagh signed a new six-year, $28.2 million contract with New York. He led all Rangers defensemen with 43 points in the 2013–14 season as the Rangers finished fifth in the Eastern Conference. The team defeated the Philadelphia Flyers, Pittsburgh Penguins and Montreal Canadiens en route to the 2014 Stanley Cup Final against the Los Angeles Kings, where the Rangers lost the series 4–1. During the playoffs, McDonagh was tied for the lead amongst defensemen in assists (13) and ranked second in points (17). For his season's efforts, McDonagh was named Rangers' MVP and the recipient of the Players' Player Award, given to the Ranger "who best exemplifies what it means to be a team player". He became just the second Rangers defenseman to hold both awards after Brian Leetch did so in the 2002–03 season.
On October 6, 2014, McDonagh was named the 27th captain in Rangers history, filling the vacancy left by Ryan Callahan the previous season. Martin St. Louis, Marc Staal, Dan Girardi and Derek Stepan were named his alternates. McDonagh became the fourth-youngest Ranger captain and 11th defenseman to hold the honor. In his first season as captain, he led his team to the Presidents' Trophy and were ultimately eliminated in the Eastern Conference Finals by the Tampa Bay Lightning in seven games. On May 30, 2015, it was revealed that McDonagh had played the final three games of the series with a broken foot.
McDonagh continued his strong play and leadership into the 2015–16 season, his second as team captain. However, during a February 6, 2016, game against the Philadelphia Flyers, McDonagh suffered a concussion after getting punched by Flyers' forward Wayne Simmonds after McDonagh cross-checked Simmonds. McDonagh missed eight games as a result, including a February 14 rematch between the two teams, during which Rangers' rookie defenseman Dylan McIlrath fought Simmonds. Still feeling the effects of the concussion, McDonagh was scratched for two games of the Rangers first round playoff series against the Pittsburgh Penguins, which the Rangers ultimately lost in five games as the Penguins eventually went on to win the Stanley Cup.
Ryan McDonagh