OBJECTIVE In the current study, we aimed to investigate the effect of smoking on inadequate response to methotrexate (MTX-IR) in rheumatoid arthritis (RA) patients. METHODS We searched PubMed, Embase, and Web of Science until 6 June 2022. Observational or interventional studies investigating MTX-IR in RA patients based on smoking status were included. Two independent reviewers assessed the risk of bias and the certainty of the evidence using the Risk of Bias in Nonrandomized Studies-of Interventions and Grades of Recommendation, Assessment, Development, and Evaluation tools, respectively. RESULTS We included 23 studies in the systematic review and 13 in the meta-analysis. Of the 13 included studies, 6 had a moderate risk, 3 had a serious risk, and 4 had a critical risk of bias. The overall random-effect meta-analysis suggested that smokers were 58% more likely to be MTX-IR when compared with nonsmokers [odds ratio (OR) 1.58, 95% confidence interval 1.21-2.06; P = .001; I2 = 69.3%]. The common-effect meta-analysis of the adjusted ORs demonstrated an overall OR of 2.69 (1.88-3.83; P < .001; I2 = 27.1%). CONCLUSIONS The current study showed that smoking is a significant predictor of MTX-IR, especially in disease-modifying antirheumatic drug-naïve early RA patients, as most of the included studies in the meta-analysis consisted of this population.