Black mothers and children experience significant health disparities in the USA. These health disparities have been attributed, in part, to experiencing racism in healthcare. This study aimed to explore how experiences of healthcare discrimination and mistreatment experienced by Black mothers may influence COVID-19 vaccine beliefs and decision-making for themselves and their families. From April 2021 to November 2021, we conducted 50 semi-structured interviews among Chicago residents. Ten participants self-identified as female and with reported children; these data were extracted from the larger sample for data analysis. Interview content included perceptions and experiences with the COVID-19 vaccine and experiences with healthcare discrimination, mistreatment, and medical mistrust. Interview transcripts were transcribed verbatim and coded using the MAXQDA 2022 qualitative software. Themes were identified using a team-based thematic analysis to understand how experiences of racism in healthcare may influence COVID-19 vaccine decision-making. Four themes were generated from the data: (1) experiences of healthcare discrimination and mistreatment, (2) distrust and fears of experimentation, (3) the influence of discrimination and distrust on COVID-19 vaccine decision-making, and (4) overcoming vaccine hesitancy. The results of this study highlight the current literature; Black mothers experience racism and discrimination in healthcare when seeking care for themselves and their children. It is evident in their stories that medical racism and historical medical abuse influence vaccine decision-making. Therefore, healthcare and public health initiatives should be intentional in addressing past and present racism in healthcare to improve vaccine distrust.