Nyberg graduated summa laude with a degree in mechanical engineering from the University of North Dakota in 1994. She continued her studies at the University of Texas at Austin, centered on human thermoregulation and experimental metabolic testing and control, and focusing on the control of thermal neutrality in space suits. This work at the Austin BioHeat Transfer Laboratory led to her doctorate in 1998.
She was selected as an Astronaut Candidate by NASA in July 2000. After two years of training and evaluation she qualified as a Mission Specialist and was assigned for technical duties in the Astronaut Office Station Operations Branch. She was Crew Support Astronaut for the Expedition 6 crew during their six-month mission on the ISS. In July 2006, Nyberg took part in NEEMO 10, a deep-sea training and simulation exercise at the Aquarius underwater laboratory to help NASA prepare for the return of astronauts to the moon and manned missions to Mars. Nyberg and her crewmates lived and worked underwater for seven days.
Nyberg was in the crew of STS-124, which flew to the ISS in May 2008. This was the second of three flights to deliver components to complete the Japanese Kibō laboratory. In May 2009, she was assigned to the STS-132 mission, which launched in May 2010, but had to be replaced three months later due to a temporary medical condition. Nyberg then served in a technical role until she received her next assignment, as a flight engineer on the Expedition 36/37.
In 2013 Nyberg served as a flight engineer on ISS Expedition 36 and Expedition 37, having launched on Soyuz TMA-09M. On the 50th anniversary on June 16, 2013 of Vostok 6, the first spaceshot by a woman, Valentina Tereshkova, Nyberg was one of only two women then in space, the other being Chinese astronaut Yaping aboard the Tiangong-1 on the Shenzhou 10 mission. In September she posted a photograph of a stuffed dinosaur she had created in orbit from space station scraps.