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The reduction of social interactions through non-pharmaceutical interventions (NPIs) has been shown to effectively curb COVID-19 transmission. However, these control measures were often accompanied by changes in people’s daily routines and constraints on their activity space, which could lead to mental distress (i.e., anxiety and depression). This study examined the interplay among individuals’ anxiety, depression, daily activities, and perceptions of COVID-19 and neighborhood cohesion. Taking Hong Kong as an example, an online survey (N = 376) was conducted to collect data from participants between March 14 to May 11, 2022. The data include respondents’ self-reported anxiety and depressive symptoms, daily activities (e.g., smartphone use), perceptions of COVID-19 (e.g., the possibility of infecting COVID-19), and perceptions of neighborhood cohesion. Using network analysis, we found that excessive smartphone use, life disturbance by COVID-19, and a community with people getting along well with each other were significant factors associated with participants’ anxiety and depression. Using critical path analysis, we observed that NPIs reduced human mobility, led to delayed bedtime, and increased smartphone use, which were associated with participants’ mental distress. We also found that NPIs and COVID-19 were associated with people’s perceptions of infection and the severity of COVID-19 and human mobility flexibility, which may further lead to mental distress. Our results also demonstrated that people with high education levels were vulnerable. These results provided important insights for designing appropriate …