Marchibroda was selected in the first round of 1953 NFL Draft by his hometown Pittsburgh Steelers as the fifth overall pick and the first quarterback selected. After one year, he left the Steelers to serve in the U.S. Army, and returned to the Steelers after his discharge. Marchibroda finished his professional playing career with the Chicago Cardinals in 1957.
Marchibroda's first head coaching appointment was with the Baltimore Colts beginning on January 15, 1975. Inheriting a 2–12 ballclub that was one of the two worst in the NFL in 1974, he led one of the two biggest turnarounds in pro football history when the Colts ended the 1975 regular season at 10–4 and qualified for the playoffs by winning the AFC East title for the first of three consecutive years. All three postseason appearances ended in divisional round losses, first to the Steelers in both 1975 and 1976 and the Oakland Raiders in 1977.
His time with the Baltimore Colts nearly lasted only a season when he resigned on September 5, 1976 in response to team owner Robert Irsay verbally abusing his players after a loss in the final preseason match to the Detroit Lions at the Pontiac Silverdome three nights earlier on September 2. Marchibroda was also at odds with general manager Joe Thomas over player personnel decisions. He was rehired two days later on September 7 after offensive and defensive coordinators Whitey Dovell and Maxie Baughan threatened to quit and the players considered boycotting practice, all in support of Marchibroda.
His five years as Colts head coach concluded with a pair of 5–11 last-place finishes in 1978 and 1979. The team was crippled by Irsay's acrimonious contract disputes with Lydell Mitchell and John Dutton which resulted in the players being traded to the San Diego Chargers and Dallas Cowboys respectively, Bert Jones' shoulder injuries that limited him to only seven games within those last two seasons and three years of questionable drafts. Marchibroda was relieved of his duties on December 27, 1979. He was succeeded by Mike McCormack on January 17, 1980.
Marchibroda served as the quarterbacks coach and later offensive coordinator of the Buffalo Bills under head coach Marv Levy from 1987 to 1991. As offensive coordinator for the Bills, he was influential in the evolution of the hurry-up offense. Levy, Marchibroda, and quarterback Jim Kelly used their version of the hurry-up offense, the "K-Gun" offense, more than any previous offense. Kelly would hurry to the line of scrimmage, preventing the defense from making substitutions, and called audibles at the line. The NFL later imposed a rule that allowed time for defense substitutions if the offense made substitutions, except after the two-minute warning of either half.
Marchibroda returned to the Colts, now based in Indianapolis, for a second stint as head coach on January 28, 1992. Similar to his first time with the franchise, the Colts had ended the previous campaign at 1–15, fired Ron Meyer after five winless games and replaced him with Rick Venturi on an interim basis. Four seasons later, the team fell a big play short of Super Bowl XXX when it lost the 1995 AFC Championship Game to the Steelers, but the playoff run did not guarantee job security for Marchibroda who parted ways with the Colts on February 9, 1996 after his demand for a contract extension of two years rather than one was rejected. Offensive coordinator Lindy Infante was promoted to succeed him on February 15.
Marchibroda's unemployment lasted only six days when he returned to Baltimore on February 15, 1996 as the first-ever head coach of a yet-to-be-named ballclub which was subsequently known as the Ravens. He replaced Bill Belichick who had been dismissed the previous day. After three losing seasons in which the Ravens went 16–31–1, Marchibroda was notified that he was not going to be retained on December 28, 1998.Brian Billick was named to succeed him just over three weeks later on January 20, 1999.