The widespread use of smartphones has significantly increased smartphone addiction among college students, especially during the COVID-19 pandemic. Since the COVID-19 outbreak, university campuses in mainland China have strictly followed the Chinese government's strict quarantine policy, including closed campus management, prohibitions against gatherings, and social distancing, increasing student loneliness and anxiety and thus increasing the risk of smartphone addiction. Extant Studies have revealed that social isolation is a prominent predictor of smartphone addiction but have failed to systematically explore the complex relationship between social isolation and smartphone addiction in the context of COVID-19; therefore, the underlying mechanisms of these factors in the post-pandemic era are unclear. This study is the first attempt to consider loneliness, COVID-19 anxiety and social isolation as a whole and to clarify the underlying mechanisms of social isolation and smartphone addiction by constructing a multiple mediating model. This study included students enrolled at eight higher education institutions in Conghua District (Guangzhou city). Quota proportional sampling was adopted, 900 self-report questionnaires were distributed through the WeChat groups of these universities from December 10 to December 15, 2022, and 868 valid questionnaires (620 females, 248 males) were ultimately obtained. The direct effect of social isolation on smartphone addiction was significant, and loneliness and COVID-19 anxiety mediated the association between social isolation and smartphone addiction in both parallel and sequential ways. Moreover, a reverse mediation model with COVID-19 anxiety as the first mediator and loneliness as the second mediator was found. College students who experience social isolation are at greater risk for smartphone addiction, and the core factor leading to their smartphone addiction is the subjective psychological state triggered by campus isolation and social distancing, such as loneliness and anxiety. These risky behaviors of people should receive extra attention, and psychological factors such as loneliness and COVID-19 anxiety should be considered in future therapies aimed at reducing addiction.