Kilrea is a nephew of former Detroit Red Wings players Wally, Ken, and Hec Kilrea. Kilrea played his first major junior season with the Hamilton Tiger Cubs in 1954-55. He had a mediocre playing career that included only 26 NHL games, although he had great success in the minor leagues. Most of Kilrea's career was spent with the AHL's Springfield Indians, for whom he was an All-Star and the career assist leader. Kilrea returned to the NHL with expansion in 1967. Kilrea has the distinction of scoring the first-ever goal for the NHL Los Angeles Kings.

After ending his playing career, Kilrea began coaching the OHL major junior Ottawa 67's in 1974. He would continue coaching the 67's until 1984, when he became an assistant coach with the defending Stanley Cup champions, New York Islanders of the NHL. However, after two seasons, he would return to coaching the 67's.

Except for a brief retirement for the 1994-95 season, Kilrea has coached the 67's ever since, and is also the General Manager of the club. He has won the Memorial Cup, emblematic of Canada's major junior championship, twice with the 67's (1984 and 1999) and is the winningest coach in junior hockey history - a task completed on January 17, 1997 with his 742nd win. To date, he has over 1000 victories.

Kilrea has also won the Matt Leyden Trophy as OHL Coach of the Year in 1980-81, 1981-82, 1995-96, 1996-97 and 2002-03. Kilrea was also honoured with the Bill Long Award in 1994 , for distinguished service to the OHL.

In 2003 Brian Kilrea was inducted into the Hockey Hall of Fame in the Builders category. The Brian Kilrea Coach of the Year Award, given annually to the top coach in the Canadian Hockey League, was renamed in his honour shortly after his induction into the Hockey Hall of Fame. Kilrea won the award in 1996-97 when it was known as the CHL Coach of the Year Award.

In twenty-nine seasons with the 67's he has only had five losing seasons - an extraordinary task in junior hockey considering the constant turnover rate of players.