The COVID-19 pandemic has exacerbated challenges for millions of students globally, leading to enrollment cliff. This study addresses the existing research gap by investigating the influence of students’ mental health and various protective factors (i.e., optimism, help-seeking behaviors, social support) on academic persistence, an indicator of student retention. We utilized the structural equation modeling approach to examine the effect of students’ mental health conditions, risk perception of COVID-19 and protective factors on academic persistence through a sample of 1,051 students from 45 states. Students’ mental health positively predicted academic persistence. Risk perception of COVID-19 was negatively associated with mental health but positively predicted academic persistence and help-seeking behaviors. Optimism fully mediated the effect of mental health on help-seeking behaviors but did not mediate the effect of risk perception on help-seeking behaviors. Social support positively predicted academic persistence. This study underscores the integral role of mental health and protective factors in supporting student retention. Universities should develop targeted programs to address students’ mental health needs and promote protective behaviors. These initiatives can enhance academic persistence, thereby aiding in the retention of students affected by this pandemic or any future global crisis.