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• Reducing modifiable risk factors could prevent the onset of cognitive decline. • Physical multimorbidity–cognitive function association was mediated by depression. • Routine screening for depression in multimorbidity patient may delay dementia onset. This paper explores the role of depressive symptoms (mediator/moderator) in the association between physical multimorbidity (exposure) and cognitive function (outcome) among older adults in the three most populous middle-income countries. This study used cross-sectional data from China (2015 China Health and Retirement Longitudinal Study), India (2017/2018 Longitudinal Ageing Study in India), and Indonesia (2014/2015 Indonesian Family Life Survey), with a total sample of 73,199 respondents aged ≥ 45 years. Three domains of cognitive tests were harmonised across surveys, including time orientation, word recall, and numeracy. The four-way decomposition analysis assessed the mediation and interaction effects between exposure, mediator/moderator, and outcome, adjusted for covariates. The mean age of the respondents (in years) was slightly younger in Indonesia (56.0, SD = 8.8) than in China (59.5, SD = 9.3) and India (60.0, SD = 10.5). The proportion of male respondents was 49.3 % in China, 47.3 % in India, and 47.5 % in Indonesia. Respondents in China had the highest mean cognitive function z scores (54.7, SD = 19.9), followed by India (51.1, SD = 20.0) and Indonesia (51.0, SD = 18.4). Physical multimorbidity was associated with lower cognitive function in China and India (p < 0.0001), with 48.4 % and 40.0 % of the association explained by the mediating effect of depressive symptoms ('overall proportion due to mediation'). The association was not found in Indonesia. Cognitive functions were lower among individuals with physical multimorbidity, and depressive symptoms mainly explained the association. Addressing depressive symptoms among persons with physical multimorbidity is likely to have not only an impact on their mental health but could prevent cognitive decline. [ABSTRACT FROM AUTHOR]