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The influence of repeated lockdowns on mental health and social isolation is unknown. We conducted a longitudinal study of the influence of repeated mild lockdowns during two emergency declarations in Japan, in May 2020 and February 2021. The analyses included 7893 people who participated in all online surveys. During repeated mild lockdowns, mental and physical symptoms decreased overall, while loneliness increased and social networks decreased. Subgroup analyses revealed that depression and suicidal ideation did not decrease only in the younger age group (aged 18–29 years) and that younger and middle-aged people (aged 18–49 years), women, people with a history of treatment for mental illness, and people who were socially disadvantaged in terms of income had higher levels of mental and physical symptoms at all survey times. Additionally, comprehensive extraction of the interaction structure between depression, demographic attributes, and psychosocial variables indicated that loneliness and social networks were most closely associated with depression. These results indicate that repeated lockdowns have cumulative negative effects on social isolation and loneliness and that susceptible populations, such as young people and those with high levels of loneliness, require special consideration during repeated lockdown situations. [ABSTRACT FROM AUTHOR]