This study aims to assess the effectiveness and safety of azilsartan-medoxomil/chlorthalidone (AZI-M/CT) compared to olmesartan-medoxomil/hydrochlorothiazide (OLM/HCTZ) in patients with hypertension. Systematic searches were conducted on PubMed, Google Scholar, and ClinicalTrials.gov, starting from their establishment until March 15, 2023. The purpose of these searches was to locate original reports that compare the effectiveness of AZI-M/CT and OLM/HCTZ in treating hypertension. Data on various characteristics at the beginning and end of the studies were gathered. The analyses were carried out using Review Manager 5.4.1 (The Nordic Cochrane Center, The Cochrane Collaboration, 2014, Odense, Denmark) and STATA 16.0 software (Stata Corp. LP, College Station, TX, USA). Risk ratios (RRs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated as part of the study. A total of 3,146 individuals from four separate investigations were included in the study, with 1,931 individuals receiving AZI-M/CT and 1,215 individuals receiving OLM/HCTZ. The combined analysis revealed that the average diastolic blood pressure (DBP) was significantly lower in the AZI-M/CT group compared to the OLM/HCTZ group (WMD -2.64 [-2.78, -2.51]; P = 0.00001; I2 = 1%). However, there were no significant differences in mean systolic blood pressure (SBP; WMD -2.95 [-6.64, 0.73]; P = 0). Furthermore, the AZI-M/CT group had a notably higher incidence of major adverse events (RR 1.58 [1.20, 2.08]; P = 0.001; I2 = 11%) and any treatment-emergent adverse events (RR 1.11 [1.03, 1.20]; P = 0.007; I2 = 51%). However, there was no significant difference in the mortality risk between the two groups (RR 0.74 [0.14, 3.91]; P = 0.72; I2 = 0%). Based on the results of our meta-analysis, AZI-M/CT is more effective than OLM/HCTZ at reducing blood pressure in elderly hypertensive patients. However, because of the small sample size, favorable results must be carefully reevaluated, and more studies are needed.