Background: Public health measures, such as social isolation, are vital to control the spread of the coronavirus disease 2019 (COVID-19), but such measures may increase the risk of depression. Thus, this study examines the influencing and moderating factors of depressive symptoms among individuals subjected to mandatory social isolation. Methods: An online cross-sectional survey was conducted to collect data from people under mandatory home or centralized social isolation in Shenzhen, China, from February 28 to March 6, 2020. The perceived risk of infection with COVID-19, perceived tone of media coverage, perceived quality of people-oriented public health services, and their depressive symptoms were assessed. Three rounds of stepwise multiple regression were performed to examine the moderating effects after controlling various variables, such as demographics, duration and venue of mandatory social isolation, infection and isolation status of family, time spent on COVID-related news, and online social support. Results: Among the 340 participants, 57.6% were men, the average age was 35.5 years old (SD = 8.37), and 55.6% held a bachelor’s degree or above. Individuals subjected to mandatory social isolation generally reported low levels of depressive symptoms. Perceived susceptibility to infection was relatively low, whereas perceived tone of media coverage was mainly positive. In terms of perceived quality of public health services, 12 (3.5%), 103 (30.3%), and 225 (66.2%) participants reported low, medium, and high quality of people-oriented services, respectively. Perceived susceptibility was positively associated with depression, whereas perceived tone of media coverage was negatively associated. The quality of people-centered public health services moderated the association between perceived risk and depressive symptoms and between perceived tone of media coverage and depressive symptoms. Conclusions: This study revealed the depressive symptoms among individuals subjected to mandatory social isolation during the COVID-19 pandemic and highlighted that frontline public health workers play a critical role in protecting public mental health.