Barber was drafted by the Flyers, seventh overall, in the first round of the 1972 draft. He was called up after 11 games in the AHL with the Richmond Robins. In his first season with the Flyers, Barber scored 30 goals and 34 assists and was a contender for the Calder Trophy for rookie of the year.
Barber was converted to left wing by coach Fred Shero. He scored at least 20 goals every season. His best season was 50 goals and 62 assists in the 1975–76 season. In the Flyers' successful 1974 and 1975 Stanley Cup playoffs campaigns, Barber contributed six goals in each, 15 and 13 points respectively. In addition to his respectable scoring abilities, Barber was also a well rounded player. On the power play he was equally valuable for setting up the play as he was for pulling the trigger, and if forced into a defensive role, he was capable. Barber said of himself, "I want to be remembered as being capable of doing my job day in and day out, not just as a goal scorer, but as a good all-around player for every kind of situation."
In the 1976 Canada Cup, Barber scored one of his most famous goals while playing for Team Canada. Behind in the final against Czechoslovakia, Barber scored to send the game into overtime, and an eventual Team Canada victory.
Barber was best known for his many years of success engaging in unsportsman-like conduct, now addressed in NHL Rule 64.1: "Any player who blatantly dives, embellishes a fall or a reaction, or who feigns an injury shall be penalized with a minor penalty under this rule."
He was a team leader for the next decade. In 1979–80, the Flyers had their record 35 game unbeaten streak, and Barber was in the centre of it all. He helped the Flyers reach the Stanley Cup finals in the spring of 1980 with a number of key playoffs goals against the NY Rangers and Minnesota North Stars.
Barber captained the Flyers in the 1981–82 season and part of 1982–83. As of the end of the 2012–13 season, he still holds the Flyers regular season career scoring record with 420 goals. He is tied for the lead for Flyers career playoffs goals with Rick MacLeish; both have 53 playoffs tallies.
Barber was forced to retire as a player after the 1984–85 season after being unable to return from reconstructive knee surgery in the spring of 1984. The Flyers retired his number 7, on October 7, 1990, just after he was inducted into the Hockey Hall of Fame.
On January 14, 2017, Barber played before a sold out crowd of over 19,000 at the Wells Fargo Center in the Flyers' 50th anniversary alumni game against the alumni of the Pittsburgh Penguins, here he played alongside his longtime linemates, Bobby Clarke and Reggie Leach, and which ended in a 3–3 tie. Before to the game Barber announced that it would be his last alumni game.
After his playing career, Barber started coaching. He coached the Hershey Bears for 16 games in 1985. He was the Flyers assistant coach between 1985–1988. After coaching the Flyers farm team (Phantoms) for four years where he won his and team's first Calder Cup in 1998. He then was the Flyers' head coach from December 2000 until April 2002, winning the Jack Adams Trophy after 2000–01. The awards ceremony was in Toronto, on live national television, and many Toronto Maple Leafs fans were in attendance. When Barber's name was announced as the winner, many Leaf fans booed the selection. Barber handled it with grace and made a joke about the popularity of the Flyers in Toronto.
Barber was the director of player personnel for the Tampa Bay Lightning, a position he held from August 2002 to June 2008. Barber's name was added to the Stanley Cup for a third time in 2004 with Tampa Bay. On October 13, 2008, he returned to the Flyers organization when he was named a scouting consultant.
Barber and his late wife, Jenny have two children, Brooks and Kerri. Jenny Barber died from lung cancer in 2001.
On September 25, 2010, the Bill Barber Sports Complex was opened in his honour in his hometown Callander.