Background: During the COVID-19 pandemic, residential lockdowns were implemented in numerous cities in China to contain the rapid spread of the disease. Although these stringent regulations effectively slowed the spread of COVID-19, they may have posed challenges to the well-being of residents. Objective: This study aims to explore the effects of residential lockdown on the subjective well-being (SWB) of individuals in China during the COVID-19 pandemic. Methods: The sample consisted of 1790 Sina Weibo users who were residents of cities that imposed residential lockdowns, of which 1310 users (73.18%) were female, and 3580 users who were residents of cities that were not locked down (gender-matched with the 1790 lockdown residents). In both the lockdown and nonlockdown groups, we calculated SWB indicators during the 2 weeks before and after the enforcement date of the residential lockdown using individuals' original posts on Sina Weibo. SWB was calculated via online ecological recognition, which is based on established machine learning predictive models. Results: The interactions of time (before the residential lockdown or after the residential lockdown) x area (lockdown or nonlockdown) in the integral analysis (N=5370) showed that after the residential lockdown, compared with the nonlockdown group, the lockdown group scored lower in some negative SWB indicators, including somatization (F-1,(5368) =13.593, P<. 001) and paranoid ideation (F-1,(5368) =14.333, P<.001). The interactions of time (before the residential lockdown or after the residential lockdown) x area (developed or underdeveloped) in the comparison of residential lockdown areas with different levels of economic development (N=1790) indicated that the SWB of residents in underdeveloped areas showed no significant change after the residential lockdown (P>.05), while that of residents in developed areas changed. Conclusions: These findings increase our understanding of the psychological impact and cost of residential lockdown during an epidemic. The more negative changes in the SWB of residents in developed areas imply a greater need for psychological intervention under residential lockdown in such areas.