Perceived social isolation is a key predictor of college students’ problematic social networking site use (PSNSU). According to the Fear-Driven/Compensation-Seeking Hypothesis, reducing the fear of social isolation and compensating for social deficits serve as negative reinforcement motivations for SNS use, which may potentially result in PSNSU. This study investigated the association between perceived social isolation and PSNSU through the mediating roles of intentional self-regulation and parasocial relationships from a compensatory perspective. Additionally, gender differences in the mediating model were examined. Findings from an online survey of 893 college students in China revealed a positive relationship between perceived social isolation and PSNSU. The serial mediation model showed that intentional self-regulation and parasocial relationships both had positive individual mediating effects, as well as a negative serial mediating effect. Moreover, these mediating effects were only significant among women. The findings suggest that in the association between perceived social isolation and PSNSU, the mediating role of intentional self-regulation forms a constructive compensatory process, while its serial mediating role through parasocial relationships forms a pathological compensatory process. Interventions for PSNSU should take the mediating role of intentional self-regulation in constructive compensation process and the gender difference into consideration.