Background <p>Neuroticism is considered the general antecedent of many specific psychopathological conditions. Even though previous studies addressed the issue of a mediated relationship by which it exerts its influence, they failed to encapsulate the changes that occur over time. Approaching the pathway between neuroticism and psychopathology from a longitudinal perspective might clarify its underlying mechanisms.</p> Methods <p>The present study aimed to address this by examining the associations between neuroticism, social-cognitive vulnerabilities (anxiety sensitivity, intolerance of uncertainty, experiential avoidance, looming cognitive style), and internalizing psychopathology (depression, anxiety, panic) in an <i>N</i> = 373 student sample. Cross-lagged Panel Model (CLPM) and Random-Intercept Cross-Lagged Panel Model (RI-CLPM) were used to test the mediation analyses in a longitudinal three-wave design.</p> Results <p>At the between-person level, the effect of neuroticism and social-cognitive vulnerabilities, such as experiential avoidance and intolerance of uncertainty, on depression and anxiety was found to be significant. An indirect effect of neuroticism was observed specifically for anxiety sensitivity and panic. No significant effects emerged at the within-person level.</p> Conclusions <p>Neuroticism and social-cognitive factors together contribute to depression and anxiety symptoms, while neuroticism’s indirect influence better explains the onset of panic at a stable, between-person level. Theoretical considerations of the results and prospective research implications are discussed.</p>