This study aimed to systematically review clinical and microbiology-related effects of ultrasonically activated irrigation (UAI) compared to syringe irrigation (SI) during endodontic treatment. Electronic databases searching and manual searching were conducted. Only randomized clinical trials (RCTs) were included comparing UAI to SI. The RoB 2.0 Cochrane tool was used for risk-of-bias (RoB) assessment. The main outcomes were postoperative pain, treatment failure, and microbiology-related outcomes. Qualitative and quantitative analyses, wherever applicable, were performed. Risk ratios (RR) and [standardized] mean differences {[S]MD} were calculated for dichotomous and continuous outcomes, respectively. Certainty of evidence (CoE) was assessed using GRADE tool. Ten RCTs were included. UAI reduced pain incidence within the first 24 h (RR 0.50, 95% CI 0.35-0.71, 308 teeth) and microbial counts (SMDpooled - 0.40, 95% CI [- 0.78, - 0.02], I2 = 0%, 126 teeth) than SI in non-vital teeth with apical periodontitis (AP). Both groups, however, had similar effects regarding pain intensity, lipopolysaccharide amounts, and the incidence of rescue-analgesic intake, treatment failure, and microbial presence (p > 0.05). CoE ranged from low to very low. Very limited evidence suggests that UAI could reduce postoperative-pain risk within the first 24 h and microbial counts for non-vital teeth with AP compared to SI. Most meta-analyses, however, are based on very few studies, mostly low-powered, with an overall very-low-to-low CoE. Further well-designed, larger RCTs are, thus, required.