For many adolescents, the COVID-19 pandemic represents a uniquely challenging period, and concerns have been raised about whether COVID-19-related stress may increase the risk for self-injurious behaviors among adolescents. This study examined the impact of pre-existing vulnerabilities on the occurrence and frequency of Non-Suicidal Self-Injury (NSSI) through COVID-19-related stress, and whether the impact of COVID-19-related stress on NSSI was buffered by the perceived social support during the pandemic. Participants were 1061 adolescents (52.40% females; Mage = 15.49 years, SD = 0.76) from a two-wave longitudinal study, which included assessments before the COVID-19 onset and one year later the declaration of the pandemic. Path analyses showed that adolescents with a prior history of NSSI, higher levels of internalizing symptoms, and poor regulatory emotional self-efficacy before the COVID-19 pandemic reported higher levels of COVID-19-related stress which in turn increased their risk to engage in NSSI. Besides, the findings did not support the role of social support as a moderator of the association between COVID-19 related stress and the occurrence/frequency of NSSI. These findings suggest that enhanced stress perception may serve as a key pathway for the continuation and development of NSSI among vulnerable adolescents facing adverse life events.