The present study explored how Black Americans who misuse opioids frame their views of spirituality/religion and locus of control (LOC). The current sample consisted of 39 Black adults residing in two urban cities in Kentucky and reported prescription opioid misuse. Using a locus of control theory as a framework, we qualitatively explored participants’ views of spirituality, religion, and opioid misuse. Structural-tabular thematic analysis (ST-TA) was used to analyze 39 interviews for three components of LOC: (1) external locus of control, (2) internal locus of control (ILC), and (3) mixed locus of control. Results indicated that participants’ religious/spiritual views shaped their beliefs related to LOC, opioid misuse, and drug recovery. Directions for future research and implications for clinicians are discussed.