In recent years, e-cigarettes as an emerging tobacco product have been favored by college students. Our study aims to explore the factors affecting the use of e-cigarettes among college students and to put forward feasible suggestions for effectively controlling the use of e-cigarettes among college students. The participating students were from three undergraduate and three specialized colleges in Guangdong Province, surveyed from January to March 2022. The Fuzzy-set Qualitative Comparative Analysis (fsQCA) method was used to analyze the influence mechanism and path of five antecedents: self-efficacy, social environment, cognition, sales environment, and negative outcome expectation, on the use of e-cigarettes. The fsQCA used in this study is a novel research methodology that combines the strengths of qualitative and quantitative analyses, through which we can determine which conditions are essential to the outcomes that lead to e-cigarette use among college students, and which combinations of conditions are more important than others. The interaction of self-efficacy, social environment, cognition, sales environment, and negative outcome expectation, affected college students' use of e-cigarettes. Through the fsQCA method, it was found that self-efficacy alone constitutes a necessary condition for college students not to use e-cigarettes. There are four possible pathways for college students not to use e-cigarettes, with higher self-efficacy, correct cognition, and a healthy social environment influencing the most important combination of conditions for college students to use e-cigarettes. The use of e-cigarettes by students in Guangdong Province is the result of the synergistic effect of multiple factors. Tobacco control action suggestions focus on improving students' self-efficacy and paying attention to the combination of different factors to achieve more effective tobacco control.