Tumor genomic profiling (TGP) is used in oncology practice to optimize cancer treatment and improve survival rates. However, TGP is underutilized among Black and African American (AA) patients, creating potential disparities in cancer treatment outcomes. Cost, accuracy, and privacy are barriers to genetic testing, but medical mistrust (MM) may also influence how Black and AA cancer patients perceive TGP. From December 2019 to February 2020, 112 Black and AA adults from two outpatient oncology sites in Philadelphia, PA without a known history of having TGP testing conducted completed a cross-sectional survey. Items queried included sociodemographic characteristics, clinical factors, patient-oncologist relationship quality, medical mistrust, and concerns about TGP. A k-means cluster analysis revealed two distinct psychographic clusters: high (MM-H) versus low (MM-L) medical mistrust. Clusters were not associated with any sociodemographic or clinical factors, except for age (MM-H patients older than MM-L patients, p = 0.006). Eleven TGP concerns were assessed; MM-H patients expressed greater concerns than MM-L patients, including distrust of the government, insurance carriers, and pharmaceutical companies. TGP concerns varied significantly based on level of medical mistrust, irrespective of sociodemographic characteristics. Targeted communications addressing TGP concerns may mitigate disparities in TGP uptake among those with medical mistrust.