Objective: This study aimed to determine the relationship between spiritual, religious, and existential well-being and self-efficacy for appropriate medication use in African American women with hypertension. Methods: In this study, we conducted cross-sectional correlations using linear regression analysis. An African American sample of women from across the United States with hypertension was chosen through a purposive sampling technique. An online survey was used. Results: There were 186 African American women with hypertension who took part in the study, with an average age of 57.15 ( SD = 12.79) years. The study found significant correlations between spiritual ( p = .022), religious ( p = .033), and existential ( p = .021) well-being and self-efficacy for appropriate medication use in African American women with hypertension. The study concluded that no women reported high spiritual, religious, or existential well-being, only moderate. Nor were they very confident that they would take their medications under changing or challenging circumstances. Conclusion: African American women are the most religious aggregate in the United States, and there is evidence that spiritual, religious, and existential well-being affects their self-efficacy for appropriate medication use. Clinicians and researchers must collaborate to enhance medication adherence through continuous education, assessment, and reinforcement while also attuning their practice to spiritual, religious, and existential well-being effects on self-efficacy for appropriate medication use in African American women.