Background: Varenicline represents the most effective first-line pharmacotherapy for smoking cessation, though post-marketing safety concerns historically limited utilisation. Contemporary evidence requires synthesis following resolution of neuropsychiatric safety signals and emerging applications in diverse populations. Objective: To evaluate varenicline efficacy and safety for smoking cessation through systematic review of evidence published January 2020-October 2025. Methods: Comprehensive search across PubMed/MEDLINE, Scopus, Web of Science, and EMBASE identified randomised controlled trials, systematic reviews, and meta-analyses. Two reviewers independently screened records using predefined PICO criteria: adults ≥18 years with current smoking status; varenicline monotherapy at standard dosing; placebo/active comparators; biochemically verified continuous abstinence ≥6 months. Data extraction captured efficacy outcomes, safety profiles, and population-specific effects. Risk of bias assessment employed Cochrane RoB 2 methodology. Results: Database searching retrieved 3,247 records, with 15 studies meeting inclusion criteria after systematic screening. Studies encompassed 8 randomised controlled trials, 4 systematic reviews/meta-analyses, 2 network meta-analyses, and 1 observational study, representing >15,000 participants across diverse populations. Varenicline demonstrated superior efficacy versus placebo across all populations, with 6-month continuous abstinence rates of 22.1% versus 8.9% (OR 3.14, 95% CI 2.21-4.46, p<0.001). Particularly robust effects were observed in cardiovascular disease patients (OR 4.12, 95% CI 2.89-5.87) and dual cigarette-e-cigarette users (OR 4.95, 95% CI 2.29-10.70). Safety analysis across >8,000 participants showed no significant increase in serious adverse events (6.8% vs 5.9% placebo, OR 1.23, 95% CI 0.95-1.59, p=0.11), including neuropsychiatric (OR 1.25, 95% CI 0.73-2.14, p=0.42) and cardiovascular events (OR 1.35, 95% CI 0.71-2.56, p=0.36). Nausea remained the most common adverse effect (28.6% vs 9.2% placebo) but proved dose-dependent and transient. Conclusions: Contemporary evidence strongly supports Varenicline as highly effective and acceptably safe first-line therapy for smoking cessation across diverse adult populations, including those with cardiovascular disease and psychiatric disorders. Historical safety concerns have been definitively resolved, supporting broader clinical implementation within established guidelines.