Introduction Hypertension, a prevalent cardiovascular disease globally, poses significant health risks and economic burden. Evolving treatment targets necessitate more intensive strategies, such as low-dose triple or quadruple drug combinations. However, a systematic comparison of different low-dose antihypertensive combinations is still lacking. The aim of the present study is to systematically and comprehensively evaluate the blood pressure-lowering effect and the associated safety of diverse low-dose polypharmacy combinations in patients with hypertension. Methods and analysis In this systematic review and network meta-analysis, randomised controlled trials comparing diverse low-dose polypharmacy combinations with placebo or active treatments in patients with hypertension will be eligible for inclusion. The primary outcomes are a reduction in systolic/diastolic blood pressure, the rate of target blood pressure, adverse effects, serious adverse effects and all-cause dropout after treatment. PubMed, Web of Science, Embase, Cochrane Library, Chinese Science Citation Database, Wanfang Medical Network, VIP Database and clinical trial registries will be systematically searched for relevant studies published from inception date to 18 January 2024. No language restrictions will be applied during the search process. Two independent reviewers will identify eligible trials and extract the data. Traditional pairwise meta-analysis will be conducted to analyse direct comparisons. A frequentist approach will be used to analyse the primary outcome for network comparisons, and cumulative rank probabilities will present the treatment hierarchy of all endpoints. Sensitivity analysis will be conducted using a Bayesian framework under a random-effects model. Subgroup analyses will be conducted according to sample size, quality of study and sponsorship, if the data allow. The Cochrane Risk of Bias Tool 2.0 will be used to assess the quality of the included studies. The Grading of Recommendations, Assessment, Development, and Evaluation system will be used to assess the strength of evidence. Ethics and dissemination Since this study relies solely on published literature, no ethics approval is necessary. The results will be submitted to a peer-reviewed journal. PROSPERO registration number CRD42024503239.