BackgroundCurrent clinical guidelines recommend either muscarinic receptor antagonists or β3-adrenoceptor agonists for overactive bladder (OAB) treatment. These recommendations, however, are primarily based on short-term (12-week) clinical trials, leaving a critical gap in evidence regarding their long-term (≥1 year) efficacy and safety. Moreover, the long-term evidence synthesized here is limited to solifenacin and mirabegron, and its generalizability to other agents remains uncertain.ObjectiveTo systematically compare the long-term efficacy and safety of solifenacin monotherapy, mirabegron monotherapy, and their combination in patients with OAB.MethodsWe systematically searched PubMed, Embase, Cochrane Library, Scopus, and ClinicalTrials.gov for clinical studies published from inception to 2 April 2026. Two reviewers independently screened, selected, and extracted data. Methodological quality was assessed using the Jadad scale and the Cochrane Risk of Bias 2 (ROB 2) tool. The primary outcomes were changes from baseline in mean volume voided incontinence episodes per 24 h, and micturition frequency per 24 h. The secondary outcome was the incidence of treatment-related adverse drug reactions Quantitative meta-analysis was performed only for safety outcomes using a random-effects model. For the primary efficacy outcomes, substantial heterogeneity (I2>58%) across the included studies precluded meaningful pooling, therefore, a narrative synthesis of efficacy data was presented.ResultsInitial screening identified 7,451 articles, of which five randomized controlled trials met the inclusion criteria. For long-term OAB management, combination therapy (solifenacin 5 mg + mirabegron 50 mg) may be more effective than each monotherapy in improving MVV and reducing mean incontinence episodes and micturition frequency. Compared to mirabegron 50mg, solifenacin 5 mg was associated with a potentially higher risk of ADRs such as dry mouth (RR 1.73, 95%CI 0.91–3.30, P = 0.10) and constipation (RR 2.46, 95%CI 1.16–5.19, P = 0.02), but a lower incidence of dizziness (RR 0.08, 95%CI 0.01–0.62, P = 0.02). Solifenacin 5 mg was associated with a lower risk of constipation and dry mouth compared to solifenacin 10 mg.ConclusionFor long-term OAB pharmacotherapy with the specific regimens evaluated, mirabegron 50 mg appears to offer a favorable profile due to its comparable efficacy and lower incidence of certain treatment-limiting ADRs. However, these findings cannot be generalized to other muscarinic receptor antagonists or β3-adrenoceptor agonists.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251056532, identifier CRD420251056532.