Cardiovascular disorders are the leading cause of death in the world. Many organ diseases (kidney, heart, and brain) are substantially more prone to develop in people with hypertension. In the treatment of hypertension, first‐line medications are recommended, while imidazoline receptor agonists are not first‐line antihypertensives. Our goal was to conduct a network meta‐analysis to assess the efficacy and safety of imidazoline receptor agonists. The meta‐analysis was performed following the PRISMA guidelines using the PICOS format, considering the CONSORT recommendations. Studies were collected from four databases: PubMed, Cochrane Library, Web of Science, and Embase. A total of 5960 articles were found. After filtering, 27 studies remained eligible for network meta‐analysis. Moxonidine reduced blood pressure in sitting position statistically significantly after 8 weeks of treatment (SBP MD: 23.80; 95% CI: 17.45–30.15; DBP MD: 10.90; 95% CI: 8.45–13.35) compared to placebo. Moreover, moxonidine reduced blood pressure more effectively than enalapril; however, this difference was not significant (SBP MD: 3.10; 95% CI: −2.60–8.80; DBP MD: 1.30; 95% CI: −1.25–3.85). Dry mouth was experienced as a side effect in the case of all imidazoline receptor agonists. After 8 weeks of treatment, the appearance of dry mouth was highest with clonidine (OR: 9.27 95% CI: 4.70–18.29) and lowest with rilmenidine (OR: 6.46 95% CI: 0.85–49.13) compared to placebo. Somnolence was less frequent with moxonidine compared to rilmenidine (OR: 0.63 95% CI: 0.17–2.31). Imidazoline receptor agonists were nearly as effective as the first‐line drugs in the examined studies. However, their utility as antihypertensives is limited due to their side effects. As a result, they are not first‐line antihypertensives and should not be used in monotherapy. However, in the case of resistant hypertension, they are a viable option. According to our findings, from the point of view of safety and efficacy, moxonidine appears to be the best choice among imidazoline receptor agonists.