Healthcare entrepreneurs (HCEs) develop and implement solutions to improve processes, structures, and practices. Unfortunately, they also operate in environments with multiple levels of uncertainty because of their industry’s unpredictable, nonlinear, and risk-averse features. Moreover, entrepreneurial uncertainty has been underexplored in the healthcare context. This empirical study examines HCEs’ uncertainty management processes throughout the entrepreneurial process. In-depth interviews were conducted with 25 for-profit and social HCEs across nine sectors in nineteen different states within the United States. We used a mixed methods qualitative approach to analyze, interpret and visualize data, including constant comparative and lexical analyses. Interview data reveals HCEs experience five major uncertainties and utilize distinct strategies to manage those uncertainties. Findings highlight the effect of external environmental conditions on HCEs’ uncertainty, the complexity and interconnectedness of HCEs’ uncertainties, their willingness to utilize a wide repertoire of strategies to cope with uncertainty, and communication’s central role in the management process. We provide practical advice to improve educational, training and professional development initiatives for aspiring, novice and experienced HCEs.