Lancaster was a talented quarterback by the time he graduated from Clairton High School, but because he was 5′5″ (165 cm), he was ignored by most college scouts. He attended tiny Wittenberg University and led its team to a 25-8-1 record between 1956 and 1959, and two Ohio Athletic Conference championships in 1957 and 1958.
By the time he graduated from Wittenberg he had grown to 5’10". His college coach had a friend with the Ottawa Rough Riders in the Canadian Football League (CFL), and Lancaster signed with them. During his rookie season in 1960, Lancaster shared the quarterbacking duties with another future Hall of Famer, Russ Jackson, and also played defensive back. The Ottawa Rough Riders won the Grey Cup that season.
In 1963 Lancaster's playing rights were sold to the Saskatchewan Roughriders for $500 with the stipulation that if Saskatchewan ever wanted to trade him, Ottawa would have the first right of refusal.
It was with Saskatchewan that "The Little General" found his stride. In 16 seasons with the Roughriders (1963–1978), he led the team into the playoffs 14 consecutive years and made it to the CFL's Western Football Conference final 12 times. During that period, Saskatchewan played for the Grey Cup five times (1966, 1967, 1969, 1972, and 1976) and won it once, in 1966, when they defeated Lancaster's former team, the Ottawa Rough Riders, 29–14.
In Lancaster's career with the Saskatchewan Roughriders, he won 170 games as quarterback, and had only one losing record, 4–11–1 in 1978, his last season as a player.
He was the first quarterback in CFL history to reach 50,000 career passing yards, won the Schenley Award as most outstanding player in 1970 and 1976, was an All-Canadian in 1970, 1973, 1975 and 1976 and a Western all-star in 1966, 1968, 1969, 1970, 1973, 1975 and 1976.
In November 2006, the Canadian sports network TSN ranked Lancaster seventh on its list of Top 50 Players of the CFL's modern era.
At the time of his death, thirty years after his retirement as a player, he was still ranked in the top three in career statistics in a number of categories:
second in touchdown passes (333, surpassed at the time only by Damon Allen) [Eight months after Lancaster's death, Anthony Calvillo moved past Lancaster into second place.]
Lancaster was a player-coach of the Saskatchewan Roughriders in the 1977 and 1978 seasons and also served as Saskatchewan's offensive co-ordinator.
He became Saskatchewan's head coach in 1979 but found, as one writer put it, that "the glorious fifties and sixties were over, and he was the first Roughrider coach in sixteen years who did not have Ron Lancaster at quarterback." The Roughriders finished 2–14 in 1979 and 2-14 in 1980. Lancaster would not coach again for eleven years.
After serving as a colour commentator for The CFL on CBC from 1981 to 1990, he became head coach of the Edmonton Eskimos on February 4, 1991. From 1991 to 1997, he had a record of 83–42 in the regular season and a Grey Cup win in 1993. He passed Hugh Campbell's team record for wins on October 27, 1996.
Lancaster signed on to the Hamilton Tiger-Cats as head coach on November 26, 1997. Between 1998 and 2003, he took the team to the Grey Cup twice (1998 and 1999), winning it in 1999. On July 10, 2006, Lancaster was re-hired as the team's head coach on an interim basis after the firing of Greg Marshall.
At the time of his death, Lancaster’s 142 career regular-season wins placed him fourth on the CFL’s career regular season wins list.
CBC Television signed Lancaster as a colour commentator on CFL broadcasts in 1980. He was part of a trio that included Don Wittman doing the play-by-play and former Argonaut head coach Leo Cahill doing colour commentary (Cahill left after the 1985 season). He was with the CBC from 1981 to 1990 and was a member of the CBC team at the 1988 Summer Olympics in Seoul, Korea as the play-by-play broadcaster for basketball.
In 2004, Lancaster was diagnosed with bladder cancer, but appeared to have beaten it after treatment. In 2008, he was diagnosed with lung cancer and immediately started treatment. Lancaster was positive in his outlook, saying, "Five years ago, I survived a battle with cancer, and now we have another battle on our hands. The goal is to get this taken care of and move forward just like I did five years ago. We will approach this the same way as then and I thank you all in advance for your kindness as I am on my path to recovery." Six weeks later, on September 18, 2008, Lancaster died of a heart attack. He was survived by his wife, Bev, his three children Lana, Ron, and Bob, and four grandchildren.
At the 2008 CFL season Awards ceremony on November 20, 2008, he was posthumously awarded the Commissioner's Award for outstanding contribution to the CFL by Commissioner Mark Cohon.