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Background Poor access to care and physician shortage are major barriers to hypertension control in sub-Saharan Africa. Implementation of evidence-based systems-level strategies targeted at these barriers are lacking. We conducted a study to evaluate the comparative effectiveness of provision of health insurance coverage (HIC) alone versus a nurse-led task shifting strategy for hypertension control (TASSH) plus HIC on systolic blood pressure (SBP) reduction among patients with uncontrolled hypertension in Ghana. Methods and findings Using a pragmatic cluster randomized trial, 32 community health centers within Ghana’s public healthcare system were randomly assigned to either HIC alone or TASSH + HIC. A total of 757 patients with uncontrolled hypertension were recruited between November 28, 2012, and June 11, 2014, and followed up to October 7, 2016. Both intervention groups received health insurance coverage plus scheduled nurse visits, while TASSH + HIC comprised cardiovascular risk assessment, lifestyle counseling, and initiation/titration of antihypertensive medications for 12 months, delivered by trained nurses within the healthcare system. The primary outcome was change in SBP from baseline to 12 months. Secondary outcomes included lifestyle behaviors and blood pressure control at 12 months and sustainability of SBP reduction at 24 months. Of the 757 patients (389 in the HIC group and 368 in the TASSH + HIC group), 85% had 12-month data available (60% women, mean BP 155.9/89.6 mm Hg). In intention-to-treat analyses adjusted for clustering, the TASSH + HIC group had a greater SBP reduction (−20.4 mm Hg; 95% CI −25.2 to −15.6) than the HIC group (−16.8 mm Hg; 95% CI −19.2 to −15.6), with a statistically significant between-group difference of −3.6 mm Hg (95% CI −6.1 to −0.5; p = 0.021). Blood pressure control improved significantly in both groups (55.2%, 95% CI 50.0% to 60.3%, for the TASSH + HIC group versus 49.9%, 95% CI 44.9% to 54.9%, for the HIC group), with a non-significant between-group difference of 5.2% (95% CI −1.8% to 12.4%; p = 0.29). Lifestyle behaviors did not change appreciably in either group. Twenty-one adverse events were reported (9 and 12 in the TASSH + HIC and HIC groups, respectively). The main study limitation is the lack of cost-effectiveness analysis to determine the additional costs and benefits, if any, of the TASSH + HIC group. Conclusions Provision of health insurance coverage plus a nurse-led task shifting strategy was associated with a greater reduction in SBP than provision of health insurance coverage alone, among patients with uncontrolled hypertension in Ghana. Future scale-up of these systems-level strategies for hypertension control in sub-Saharan Africa requires a cost–benefit analysis. Trial registration ClinicalTrials.gov NCT01802372, In a cluster randomized trial, Gbenga Ogedegbe and colleageues examine the effectiveness of a nurse-led task shifting strategy for hypertension control in Ghana, Author summary Why was this study done? The burden of cardiovascular diseases in sub-Saharan Africa (SSA) is growing due to an increased prevalence of uncontrolled hypertension. Poor access to healthcare and physician shortage are major barriers to hypertension control in SSA. Implementation of evidence-based systems-level strategies targeted at these barriers are lacking. What did the researchers do and find? In this cluster randomized controlled trial conducted among 757 patients across 32 community health centers in Ghana, we examined whether the addition of a nurse-led intervention for hypertension control to health insurance coverage led to a greater reduction in systolic blood pressure (BP) than provision of health insurance coverage alone. We found that the addition of a nurse-led intervention to provision of health insurance coverage led to a greater reduction in systolic BP (−20.4 mm Hg) than health insurance coverage alone (−16.8 mm Hg), with a net difference in reduction of 3.6 mm Hg (p = 0.021) at 12 months. What do these findings mean? The study findings provide evidence for policy makers to recommend addition of a nurse-led task shifting strategy for hypertension control to health insurance coverage for management of hypertension in SSA. Future scale-up of this nurse-led strategy in SSA would require a cost–benefit analysis and establishment of a policy that grants nurses prescribing power to treat patients with uncomplicated hypertension, similar to current policy for treatment of HIV.