Born and raised in the Boston area, Brian Duffy graduated from the United States Air Force Academy with a Bachelor of Science degree in Mathematics in June 1975.  He graduated from the Air Force's Undergraduate Pilot Training program in August 1976 where he was named a Distinguished Graduate, awarded the Flying Training Award, and assigned to fly the F-15.  He completed two operational tours in the F-15 before attending the U.S. Air Force Test Pilot School at Edwards AFB, California.  Duffy graduated as a Distinguished Graduate and was assigned as the Director of F-15 Flight Test at Eglin AFB, Florida.  He led a cadre of experienced test and operational pilots and managed a fleet of highly modified aircraft.

Out of thousands of applicants, Duffy was one of thirteen selected by NASA to be Astronaut Candidate in 1985 and became an astronaut in 1986.  Following the Challenger accident, he was a member of the team that redesigned and tested the field and nozzle joints of the Redesigned Solid Rocket Motor.

Duffy's first space flight was as the Pilot of the Space Shuttle Atlantis for the ATLAS-1 mission, STS-45.  It was the first of a series of missions conducted to study the sun, the atmosphere, and the complex interactions between them.  During one of the experiments of the mission, the crew created the first man-made aurora.