Background: Cytisine has demonstrated significant efficacy for smoking cessation, yet diverse dosing regimens have led to clinical uncertainty. To clarify whether variations in dosing duration and frequency influence therapeutic outcomes, we conducted a systematic review and network meta-analysis (NMA) evaluating the comparative efficacy and safety of different cytisine regimens against placebo.Methods: We searched PubMed, EMBASE, Scopus, MEDLINE, and the Cochrane Library through February 7, 2026. Eligible studies included randomized controlled trials (RCTs) and observational studies involving adults intending to quit. The primary outcome was continuous abstinence at 24 weeks (CAR24); secondary outcomes included CAR12, CAR48, point prevalence abstinence (PAR12, PAR24, PAR48), and adverse events. A random-effects NMA was performed. (PROSPERO: CRD420261320145).Findings: Seventeen RCTs (n=11,643) and nine observational studies (n=4,793) were analyzed. Regarding the primary outcome (CAR24), fixed-dose regimens of 3 mg three times daily for six and twelve weeks (CYT_3TID_6WK and CYT_3TID_12WK) demonstrated significant superiority over placebo, with CYT_3TID_12WK yielded the highest effect (RR 3·53, 95% CI 1·74–7·15). In contrast, the traditional 25-day titration regimen (CYT_RDT_25D) did not differ significantly from placebo (RR 1·64, 95% CI 0·90–3·00). Observational data supported these findings, showing higher odds of quitting with longer fixed-dose strategies. When compared to active controls, CYT_RDT_25D was superior to nicotine replacement therapy for self‑reported CAR24 (adjusted OR 2·54, 95% CI 1·72–3·74). Safety profiles were comparable, with sleep disturbances and gastrointestinal events reported most frequently; no severe safety concerns emerged.Interpretation: Cytisine efficacy appears regimen-dependent. Extended six- and twelve-week fixed-dose regimens offer more durable abstinence than the traditional 25-day titration. Despite variability in study quality, longer fixed-dose regimens represent promising clinical options, though further head-to-head trials are warranted to optimize dosing.