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Introduction: Tobacco use, which is directly responsible for 10% of total deaths per year globally, remains consistently high, with approximately 20% of the population reporting regular consumption globally. Moreover, health disparities regarding tobacco consumption and smoking cessation are growing between rural and urban populations worldwide. Social media interventions for tobacco cessation may effectively reach both groups. The objective of this study was to evaluate the efficacy of a WeChat-delivered smoking cessation intervention among rural and urban Chinese smokers, and to assess moderating variables that may contribute to differential intervention efficacy. Methods: WeChat was used to recruit smokers into this intervention study between 1 July and 5 August 2019. Participants were randomized to one of three intervention schedules: participants in the Standard Group and the Enhanced Group received 20 smoking-related messages over 2 weeks, whereas participants in the Enhanced Group received an extra 6 oral health-related messages for one week. Participants in the control group received 20 smoking-related messages after the post-intervention assessment. Participants completed questionnaires at baseline and at 4 weeks follow-up. Our primary outcome was smoking cessation stage of change and secondary outcome was 24-h point prevalence abstinence (PPA). Urban and rural areas were based on self-reported living areas. Chi-squared test, Fisher’s exact test, ANOVA test, linear regression, and logistic regression were used for analysis. Results: Overall, 403 participants completed the intervention (233 rural, 107 suburban, 63 urban). Compared to urban participants, rural participants were more likely to have progressed to a later stage of change (β = 0.40, 95% CI: 0.13, 0.67) and to report higher 24-h PPA rates at follow-up (aOR = 3.23, 95% CI: 1.36, 7.68). After stratification by living area, the intervention effects in stage of change and 24-h PPA rate at follow-up were only found in the urban subgroup. Discussion: Smokers who lived in rural areas reported better smoking cessation outcomes compared with urban smokers, however, the efficacy of a WeChat-based smoking cessation intervention was only found for participants living in an urban area. WeChat based smoking cessation interventions should be used to promote smoking cessation in urban, suburban, and rural areas.