Calvin Bridges was born in Schuyler Falls, New York. He was orphaned at an early age, and raised by his grandparents. In 1909, after attending one of the few courses taught by Thomas Hunt Morgan, Bridges joined Morgan's lab at Columbia to do research in the new field of genetics. A freshman at the time, Bridges was given the lowly job of washing out the fly bottles. As legend has it, Bridges found the first Drosophila mutant, the white-eyed fly, just as he was about to wash out one of the bottles. According to his lab mate, Alfred Sturtevant, Bridges had the best "eyes" in the lab for finding new Drosophila mutants and the most skill and patience for building new strains for testing. Many of these Drosophila strains are still in use today.

Bridges was also very inventive. He developed a cheaper fly-food mix to replace bananas. He designed the binocular microscope for examining flies, and he also designed the temperature-regulated incubators to grow the flies in.

Some of Bridges' scientific credits include the theory of chromosomal non-disjunction (non-segregation of paired chromosomes), setting up the nomenclature system for naming fly mutants and providing most of the data correlating Drosophila genes with banding patterns in salivary chromosomes.

In 1928, Bridges moved with Morgan to the California Institute of Technology, though he retained his position as research associate at Columbia. In a biography, Thomas Hunt Morgan wrote of Bridges that "he was simple and unaffected and always helpful to anyone who came to him for advice." In 1938, Bridges died of heart failure due to complications from a heart valve infection.