MacDonald developed his skills in his native Nova Scotia, and after playing two seasons of Junior A hockey with the Truro Bearcats of the Maritime Hockey League, he signed with Moncton of the Quebec Major Junior Hockey League in 2005 as a 19-year-old.

In 2005-06, he had 46 points (six goals, 40 assists) in 68 games, and had 13 points (two goals, 11 assists) in 21 playoff games to help Moncton win the QMJHL championship.

The New York Islanders selected MacDonald in the sixth round (No. 160) of the 2006 NHL Draft. He returned for a second season with Moncton in 2006-07, when he had 58 points (14 goals, 44 assists) in 65 games and was named to the QMJHL First All-Star Team.

He signed an entry-level contract with the Islanders on May 24, 2007, and split his first professional season between Utah of the ECHL and Bridgeport of the American Hockey League.

MacDonald made his NHL debut against the Buffalo Sabres on Feb. 28, 2009. He played three games and didn't have a point before being returned to Bridgeport.

He started 2009-10 in the AHL but was called up to the NHL again in November and stayed there the rest of the season. He scored his first NHL goal against the New York Rangers in a 5-2 loss at home on Dec. 17, 2009. He had seven points (one goal, six assists) in 46 games, but set the tone for his career by averaging 2.0 blocked shots per game, tops among rookies to play at least 40 games.

In 2010-11, he led Islanders defensemen with 27 points (four goals, 23 assists), a plus-9 rating and 160 blocked shots.

MacDonald was traded to the Philadelphia Flyers on March 4, 2014, for center Matt Mangene, a third-round pick in the 2014 NHL Draft and a second-round pick in 2015. He finished 2013-14 with a new NHL high of 28 points (four goals, 24 assists) and led the League with 242 blocked shots in 82 games.

On April 15, 2014, he signed a six-year, $30 million contract with the Flyers that runs through 2019-20.