Some of the earliest and most influential women scientists in the U.S. have been Catholic sisters. Yet their stories and scientific contributions are not widely known. Why did these sisters pursue scientific study, in what ways did they contribute to science, and how did their experiences compare to that of other women scientists? Using archival data from women’s religious communities to which they belonged and universities where they were employed, this qualitative multiple case study explored the occupational motivations, scientific contributions, and experiences of three U.S. Catholic sister scientists. Similarities between the experiences of sister scientists and other women scientists included mentoring, marginalization, and religious discrimination. What differed in the experiences of sister scientists was their financial obligation to and support from their religious communities, and their regard of science as worship. This article brings to light the significant scientific contributions of three Catholic sister scientists as a way to honor their previously overlooked work and to document their lived experiences for the benefit of other women in STEM and those considering a career in STEM.