Introduction: Theoretical approaches suggest that adaptability and well-being could serve as protective factors in influencing mental health. However, it remains empirically unclear how students' prior adaptability and well-being predict depression (and vice versa) in the long term. Hence, using a longitudinal design, the present study explores the reciprocal relations among university students' adaptability, well-being, as well as depression before, during, and after the lockdown resulting from the COVID-19 pandemic. Methods: In a sample of 7527 Chinese university students (51.7% female; mean age = 18.38, standard deviation [SD] = 0.77), we measured adaptability, university-related well-being, and depression. Self-report assessments were administered before (Time 1, October 2019), 1 year after (Time 2, March 2021), and 2 years after (Time 3, March 2022) the COVID-19 outbreak in a comprehensive public university in China. Results: Cross-lagged panel analysis revealed that prior adaptability and university-related well-being negatively predicted subsequent depression, even when statistically controlling for demographic factors such as gender, family economic status, and so on. Moreover, results showed positive reciprocal relations between adaptability and university-related well-being. Conclusions:Findings indicate that adaptability and university-related well-being have long-term protective effects on the mental health of university students, which could mitigate the negative effects of COVID-19 or other crises. The implications for practice and suggestions for future research are discussed.