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Background Home working has increased since the Coronavirus Disease 2019 (COVID-19) pandemic’s onset with concerns that it may have adverse health implications. We assessed the association between home working and social and mental wellbeing among the employed population aged 16 to 66 through harmonised analyses of 7 UK longitudinal studies. Methods and findings We estimated associations between home working and measures of psychological distress, low life satisfaction, poor self-rated health, low social contact, and loneliness across 3 different stages of the pandemic (T1 = April to June 2020 –first lockdown, T2 = July to October 2020 –eased restrictions, T3 = November 2020 to March 2021 –second lockdown) using modified Poisson regression and meta-analyses to pool results across studies. We successively adjusted the model for sociodemographic characteristics (e.g., age, sex), job characteristics (e.g., sector of activity, pre-pandemic home working propensities), and pre-pandemic health. Among respectively 10,367, 11,585, and 12,179 participants at T1, T2, and T3, we found higher rates of home working at T1 and T3 compared with T2, reflecting lockdown periods. Home working was not associated with psychological distress at T1 (RR = 0.92, 95% CI = 0.79 to 1.08) or T2 (RR = 0.99, 95% CI = 0.88 to 1.11), but a detrimental association was found with psychological distress at T3 (RR = 1.17, 95% CI = 1.05 to 1.30). Study limitations include the fact that pre-pandemic home working propensities were derived from external sources, no information was collected on home working dosage and possible reverse association between change in wellbeing and home working likelihood. Conclusions No clear evidence of an association between home working and mental wellbeing was found, apart from greater risk of psychological distress during the second lockdown, but differences across subgroups (e.g., by sex or level of education) may exist. Longer term shifts to home working might not have adverse impacts on population wellbeing in the absence of pandemic restrictions but further monitoring of health inequalities is required. Jacques Wels and colleagues investigate the relationship between working from home and different indicators of mental and social wellbeing in the UK. Author summary Why was this study done? ➢ The number of workers working from home drastically increased during the Coronavirus Disease 2019 (COVID-19) pandemic. ➢ Little is known about the relationship between home working and mental and social wellbeing before and during the pandemic. ➢ As some home working schemes are likely to remain post-pandemic, understanding this association is important. What did the researchers do and find? ➢ We analysed data from 7 UK-based population surveys to better understand the relationship between working from home (partially or fully) and different indicators of mental and social wellbeing. ➢ We analysed these relationships over 3 time points—i.e., April to June 2020 (T1), July to October 2020 (T2), and November 2020 to March 2021 (T3)—and controlled for sociodemographic (e.g., age, sex, and ethnicity) and job characteristics (e.g., sector of activity, key worker status). ➢ We found that home working was not associated with psychological distress at T1 or T2, but at T3 it was associated with increased psychological distress (relative risk = 1.17, 95% CI = 1.05 to 1.30). No other meaningful associations were found. ➢ We stratified these associations by sex, education level, age, and full-time versus part-time employment and found that home working was associated with greater psychological distress in those with lower than degree level education. What do these findings mean? ➢ We found no clear evidence of a lasting association between home working, mental health, and social wellbeing which may indicate that, during the pandemic, home working was not detrimental nor beneficial for workers’ wellbeing. ➢ Differences across subgroups may exist and specific impacts by sex, age, and education level need to be investigated further.