Colin Miller was selected by the Los Angeles Kings in the fifth round (No. 151) of the 2012 NHL Draft after his second season with his hometown team, Sault Ste. Marie of the Ontario Hockey League, where he had 28 points (eight goals, 20 assists) in 54 games.

The 6-foot-1, 193-pound defenseman would play one more season of junior hockey with Sault Ste. Marie, getting 55 points (20 goals, 35 assists) in 54 games and received the Mickey Renaud Captain's Trophy, given to the OHL team captain that best exemplifies leadership on and off the ice, with a passion and dedication to the game of hockey and community.

Miller played the next two seasons with Manchester of the American Hockey League, including in 2014-15, when he was named an AHL Second All-Star Team after he had 52 points (19 goals, 33 assists) in 70 games. At the 2015 AHL All-Star Skills Competition, Miller won the fastest skater competition (13.805 seconds) and set a then event record for hardest shot at 105.5 mph.

He stepped up his game in the playoffs that season, getting 10 points (two goals, eight assists) in 19 games while anchoring Manchester's defense to help it win the Calder Cup.

However, with the Kings set on defense, Miller was traded to the Bruins on June 26, 2015. He split the following season between Boston and Providence of the AHL, then stuck with the Bruins for the entirety of the 2016-17 season, finishing with 13 points (six goals, seven assists) in 61 games.

But Miller was left unprotected and was selected by the Vegas Golden Knights in the 2017 NHL Expansion Draft. During Vegas' inaugural season in 2017-18, Miller broke out, leading its defenseman in goals (10), points (41), power-play goals (five) and power-play assists (17). He kept up his strong play in the Stanley Cup Playoffs, getting seven points (three goals, four assists) in 20 games to help the Golden Knights advance to the Cup Final.

Miller played one more season with Vegas before he was traded to the Buffalo Sabres for two draft picks on June 29, 2019.

In his first season in Buffalo, Miller had 11 points (one goals, 10 assists) in 51 games before the season was paused on March 12 due to concerns surrounding the coronavirus. He played the 2022-23 season for the Dallas Stars before he was traded to the New Jersey Devils on July 1, 2023. He had eight points (four goals, four assists) for the Devils before he was traded to the Winnipeg Jets on March 8, 2024 for a fourth-round pick in the 2026 NHL Draft. He re-signed with Winnipeg on July 1, 2024.