Poor adherence to antihypertensive therapy is a major cause of poor blood pressure (BP) control in patients with hypertension. Regimen simplification may improve adherence and BP control. This systematic review assessed whether single-pill combination (SPC) therapy led to improved adherence, persistence, and better BP control compared with free-equivalent combination (FEC) therapy in patients with hypertension. PubMed, Medline, Embase, and the Cochrane Library were searched until July 2020, in addition to manual searching of relevant congress abstracts from 2014 to 2020 for studies including adults with hypertension aged ≥18 years receiving SPC or FEC antihypertensive therapy measuring any of the following: adherence, persistence, and reductions in systolic BP and/or diastolic BP. Adherence and persistence were summarized in a narrative analysis; direct pair-wise meta-analysis was conducted to compare BP reductions with SPC therapy versus FEC therapy using fixed-effect and random-effects models. Following screening, 44 studies were included. The majority (18 of 23) of studies measuring adherence showed adherence was significantly improved in patients receiving SPCs versus FECs. Overall, 16 studies measured persistence, of which 14 showed that patients receiving SPCs had significantly improved persistence or were significantly less likely to discontinue therapy than patients receiving FECs. Systolic BP (mean difference, −3.99 [95% CI, −7.92 to −0.07]; P =0.05) and diastolic BP (−1.54 [95% CI, −2.67 to −0.41]; P =0.0076) were both significantly reduced with SPC therapy compared with FEC therapy at week 12. SPC therapy leads to improved adherence and persistence compared with FEC therapy and may lead to better BP control in patients with hypertension.