The mechanism of COVID-19’s impact on the quality of life of adolescents over time remains elusive and inconclusive. To better explore the dynamics of the epidemic’s impact, a comparative cross-sectional survey was conducted at the beginning stage (Time 1) and after lifting (Time 2) Wuhan’s citywide quarantine in Hubei Province. The total sample size was 10,116. The results showed that among biological factors, the quality of life of adolescents with poorer health status was significantly impaired at both time points, while female adolescents were more fragile merely at the beginning stage. Psychological factors, such as self-efficacy and resilience have both short and long-term effects on promoting adopt changes in their daily lives. Anxiety as an instant negative indicator of the quality of life was only significant in Time 1. As social factors, lower social class and perceived stigma negatively impacted their quality of life continuously. Meanwhile, adolescents with higher education levels were significantly related to a worse quality of life in Time 2. Within the framework of the biopsychosocial model, self-efficacy, resilience, and de-stigmatization strategies were the targets for maintaining and promoting the quality of life among adolescents.