Migrant workers in China are experiencing social isolation caused by institutional and non-institutional barriers. This paper explores the relationship between social isolation and migrants’ smoking behavior as well as gender differences in smoking. Migrants’ social isolation is systematically measured from the structural and qualitative perspective. Using the survey data of 2,188 rural-to-urban migrants in China in 2016, the prevalence of smoking among migrants is 38.21%, with 51.70% for males and 4.06% for females. Migrants with social isolation, such as migration instability, lack of ties with family and fellow migrants, and life dissatisfaction in migrant cities, are more likely to smoke and the impacts vary by gender. The income and price elasticities of cigarette demand show that male migrant smokers are more sensitive to income and price changes than female migrant smokers. Boosting rural migrants’ integration into the local community will reduce smoking prevalence, improving the overall health of the society.