Evidence from high-income countries suggests that depressive symptoms may mediate the relationship between smoking and pain. However, the relationship remains poorly understood for the population in low- and middle-income countries (LMICs), who account for 80% of the current tobacco consumers. Using cross-sectional data from a nationally representative longitudinal survey in China, this study conducted the mediation analysis within the structural equation model (SEM) framework. It tested the indirect effect using the Monte Carlo method. Among the 16,575 participants, 29.2% (n = 4,839) reported being current smokers, 8.5% (n = 1,412) being former smokers, and 62.3% (n = 10,324) being never smokers. Phenotypic characteristics of smokers revealed some distinct characteristics concerning smoking rates, gender, and education attainment compared with results from high-income countries. Besides, current smokers reported significantly higher pain severity than never and former smokers and more depressive symptoms compared with never smokers. The mediation analysis indicated that the self-reported pain was mediated by depressive symptoms 62.7% of the association with smoking and 82.1% of the connection to the number of years quit. However, no mediation effect of depressive symptoms was found for the relationship between the amount smoked and pain severity. This study may fill the literature gap in examining depressive symptoms’ mediating role in the relationship between smoking and pain severity for LMICs.Copyright © 2021 Elsevier Ltd. All rights reserved.