Nicknamed "Petro", as a junior, he played with the Niagara IceDogs and Barrie Colts of the Ontario Hockey League (OHL).

[3] The Jr. Canadiens won Ontario's bantam championship in 2005, with Pietrangelo scoring the game-winning goal in the final against the Markham Waxers.

[5] He scored at a near point-per-game pace in his rookie season with the IceDogs with 52 points in 59 games, then moved with the team to Niagara as the franchise relocated in 2007.

[13] Three days later, however, he suffered a head injury on October 13 in a game against the Toronto Maple Leafs, when Ryan Hollweg checked him from behind into the boards.

[14] Pietrangelo returned shortly, and after playing eight games total for the Blues, he was sent back to his junior team, the Niagara Icedogs.

In 2010–11, Pietrangelo played his first full season with the Blues, leading all team defencemen with 43 points (11 goals and 32 assists) over 79 games.

[18] Comparatively, the league's leading scorer among rookie defencemen that season was teammate Kevin Shattenkirk, who was born a year earlier than Pietrangelo; he also recorded 43 points.

Pietrangelo was selected to play in his second All-Star Game, along with Blues teammates Ryan O'Reilly, David Perron and Jordan Binnington.

In the final year of his contract with free agency impending, Pietrangelo and the Blues were unable to come to terms on a contract extension, and the two parties ultimately broke off negotiations, making Pietrangelo a free agent for the first time in his career; the main point of contention was that Pietrangelo was looking for a full no movement clause (which was personally important for Pietrangelo as he has four children all under the age of 3 years old at the time of his free agency and wanted guaranteed stability of not having to move teams via trade or waivers[24][25]), which Blues general manager Doug Armstrong refused to give (Armstrong has a consistent history of never handing out full no move clauses to any of his players).

[29] With help from actor Jon Hamm, Pietrangelo won the Breakaway Challenge portion of the All-Star Skills Competition despite missing both of his shots.

[30] Pietrangelo took time away from the team midway through the 2022–23 season after his daughter was suffering from a brain lesion, and briefly contemplated retirement.

[34][35] The Golden Knights ultimately defeated the Panthers in five games, and Pietrangelo hoisted the Stanley Cup for the second time in his career.

He was named a Tournament All-Star by the media, the Best Defenceman by the directorate and was selected by the coaching staff as one of Canada's top three players.

As the St. Louis Blues failed to make the playoffs in Pietrangelo's first full season in the NHL, he was selected to Canada's men's team for the 2011 IIHF World Championship in Slovakia.

On October 3, 2021, Pietrangelo was one of the first three players named to the men's hockey roster for Canada's team for the 2022 Winter Olympics in Beijing, alongside Sidney Crosby and Connor McDavid.

[42] However, due to the NHL's subsequent decision not to attend the Beijing Games as a result of the Omicron variant's impacts on scheduling, Pietrangelo was unable to compete.

[43] Pietrangelo was born to parents Joe and Edy, and raised along with his older brother David in King City.

[51] In September 2022, one of their children developed encephalitis; the ordeal caused Pietrangelo to miss nine games in the 2022–23 season and briefly contemplate retirement, though she made a recovery by the end of the year.