Kalpana attended Tagore Baal Niketan School in Karnal from which she graduated in 1976. Growing up in Karnal she watched light airplanes and gliders fly overhead to and from the nearby municipal airport from which she eventually made her first flight. Kalpana's interest grew into a determination to pursue a career in aviation.

Kalpana earned a Bachelor's Degree in Aeronautical Engineering from Punjab Engineering College, affiliated with Punjab University on 15 July 1982. She also served as Secretary of the Aeronautical and Astronautical Society while at the college.

Kalpana enrolled at the University of Texas at Arlington in September 1982. In December 1983, she married Jean-Pierre Harrison, a neighbour who she met immediately after arriving in the United States. Kalpana graduated in 1984 with a Master's Degree in Aerospace Engineering. While in Arlington, Kalpana took her first flying lessons annd pursued interests in SCUBA diving among other outdoor activities.

The outdoors was for Kalpana a great source of strength and inspiration. She marvelled at nature, and though having no interest in religion, felt and acted upon a profound spiritual kinship with creation.

In September 1984 Kalpana enrolled in the University of Colorado in Boulder where she earned a second Master's Degree and Ph.D. in Aerospace Engineering, the latter awarded in 1988. While in Boulder, Kalpana earned Private Pilot licenses for both single-engine airplanes and gliders; she also participated extensively in outdoor activities including hiking, cross-country skiing and rafting down mountain streams. Though the Space Shuttle Challenger and its crew were lost during this time, Kalpana began to consider applying for the U.S. astronaut corps when the opportunity presented itself.

After completing her Ph.D. Kalpana left Boulder to take up a position as a research scientist specializing in computational fluid dynamics at NASA Ames Research Center in Sunnyvale, California. She worked on airflow simulations around various bodies including a descending delta in ground-effect to better understand the performance of VSTOL aircraft such as the Harrier. An image of this latter simulation has been on display at the Smithsonian National Air and Space Museum for several years.

Kalpana became a U.S. citizen in 1990. She also continued pilot training, eventually earning a Commercial Pilot license in single and multi-engine airplanes,seaplanes and gliders, an instrument rating in airplanes, and Certificated Flight Instructor ratings in airplanes and gliders.

Kalpana applied for the NASA astronaut corps in 1992 after seeing an official solicitation. In 1993 she received notice from Johnson Space Center instructing her to undergo an FAA pilot medical examination. Though this notice indicated Kalpana's application had progressed quite far it went no further that year. Over the next year she kept her application updated whenever she acquired any significant new qualification. In the summer of 1994 Kalpana was invited to undergo a full interview at Johnson Space Center after which she awaited word on the success of her application. In December 1994 Kalpana received a telephone call from Johnson Space Center inquiring "if you still want to come and work for us."

Kalpana reported for astronaut candidate training at Johnson Space Center in March 1995 as member of a class renamed Flying Escargots at the suggestion of a French astronaut who was not too keen on the original assigned name of Slugs. The next 15 months were filled with studies of space shuttle systems, T-38 jet operations, survival training in various environments, professional responsibilities, Russian language training, and many other subjects necessary to qualify for assignment to a space flight. Graduation in the summer of 1996 led to technical jobs in the astronaut office until she was assigned to the crew of STS-87 later that year.

The STS-87 mission flew aboard Space Shuttle Columbia during November - December 1997 during which Kalpana was responsible for various experiments and the SPARTAN satellite. The crew of STS-87 included Takao Doi, the first Japanese astronaut to conduct an spacewalk, and Leonid Kadenyuk, the first astronaut from independent Ukraine. Following the flight, the crew of STS-87 conducted tours of Japan and Ukraine in 1998.

Once the post-flight activities concluded, Kalpana was assigned technical responsibilities in the International Space Station program. She received an award from the astronaut office for her outstanding efforts in this position. During this period Kalpana became involved with the International Space School Foundation, founded by a businessman local to the Johnson Space Center area. Kalpana suggested the inclusion of Tagore Baal Niketan School which has since sent two students per year to participate in the summer sessions.

In late 2000, Kalpana was assigned to the crew of STS-107 which included Israel's first astronaut, Ilan Ramon. STS-107 was the last pure science mission to be flown aboard the space shuttle, all other shuttle flights scheduled for construction of the International Space Station. STS-107 was flown aboard Columbia since it was the only space shuttle not fitted with the space station docking mechanism. For various reasons, including scheduling and technical, the mission launch date slipped repeatedly until Columbia finally lifted off from Kennedy Space Center on 16 January 2003.

STS-107 was a very successful mission and met all of its science objectives. A vast amount of data was transmitted to Earth, and yet still more was recovered from the Columbia debris field.

Kalpana once stated in an interview:

"I pretty much had my dreams, like anybody else and I followed them. People around me fortunately always encouraged and said 'if that's what you want to do carry on'."