<p>A number of studies have shown that individuals perceived greater stress and had higher levels of depression during the COVID-19 lockdown. However, little is known about how individuals’ perceived stress affects their depression levels during the public health emergencies (e.g., COVID-19) lockdown, and even fewer studies have explored the factors that buffer the effects of perceived stress on depression during the lockdown. This study combined a simulated lockdown scenario experiment with a questionnaire during a real COVID-19 lockdown to investigate whether a negative outlook mediated the association between perceived stress and depression, and whether trait gratitude played a protective role. The results revealed that a negative outlook served as a mediator linking perceived stress to depression both in the simulated lockdown scenario and during the real COVID-19 lockdown, and that trait gratitude could buffer both the effects of perceived stress on depression and the effects of a negative outlook on depression during the lockdown. This study not only enriched the understanding of the mechanisms of depression development during the lockdown against public health emergencies, but also revealed that we could reduce the negative impacts of sudden public health crisis events on individuals’ mental health through gratitude practice.</p>