<p>Long-term smokeless tobacco is associated with various adverse health problems. The objective of the current systematic review and meta-analysis was to evaluate the overall efficacy of pharmacotherapy. A systematic search was conducted across PubMed, Cochrane, Lilacs, EBSCO host and Scopus databases. The inclusion criteria were smokeless tobacco users. The data was extracted by two independent investigators. Smokeless tobacco cessation intervention analyses were conducted using keywords like mobile-health, nicotine gum, nicotine replacement therapy(NRT), interventions, nicotine lozenge and others. Furthermore, the efficacy was evaluated and risk ratio, ROB2 risk of bias, subgroup analysis were done and quit rates were assessed. We found papers to be reviewed in order to be included in the research. The meta-analysis and systematic review included twenty randomized clinical trials. Out of the total 20 studies, 8 studies favoured pharmacotherapy, the effect size being Z = 4.76 and I2 = 45% showing moderate heterogeneity. Combined treatments with behavior counselling proved to be more efficient than the placebo and monotherapies in assisting participants to attain abstinence. The most effective of these, estimated were Bupropion and Varenicline in combined with behavior counselling. The quitting of smokeless tobacco is complex and requires more than just a medication. A combined approach that includes pharmacological support, behavioral strategies, and strong public health efforts is likely to be more effective. Tobacco cessation needs holistic approach. The evidence, though promising, is limited by study variability, and inconsistent outcome reporting.It is recommended to conduct multicentric trials to confirm these findings, comparing standardized medication with dose modifications and larger sample size. <i>Prospero Registration Number</i>: (PROSPERO) (CRD42022302266)</p>