Objective: An overview, meta-analysis, and trial sequential analysis were conducted to evaluate the efficacy and safety of varenicline for smoking cessation. Methods: Systematic reviews (SRs) and randomized controlled trials evaluating varenicline versus placebo for smoking cessation were included. A forest plot was used to summarize the effect size of the included SRs. Traditional meta-analysis and trial sequential analysis (TSA) were performed using Stata software and TSA 0.9 software, respectively. Finally, the Grades of Recommendation, Assessment, Development, and Evaluation approach was used to assess the quality of evidence for the abstinence effect. Results: A total of 13 SRs and 46 randomized controlled trials were included. Twelve review studies showed that varenicline was superior to placebo for smoking cessation. The meta-analysis results showed that, compared with the placebo, varenicline significantly increased the odds of smoking cessation (odds ratio = 2.54, 95% confidence interval = 2.20-2.94, P < 0.05, moderate quality). Subgroup analysis showed that there were significant differences in smokers with disease and general smokers (P < 0.05). Differences were also found in the follow-up time at 12, 24, and 52 weeks (P < 0.05). The common adverse events were nausea, vomit, abnormal dreams, sleep disturbances, headache, depression, irritability, indigestion, and nasopharyngitis (P < 0.05). The TSA results confirmed the evidence for the effect of varenicline on smoking cessation. Conclusions: Existing evidence supports the superiority of varenicline over a placebo for smoking cessation. Varenicline had mild to moderate adverse events but was well tolerated. Future trials should investigate varenicline in combination with other smoking cessation approaches and compare it with other interventions.