Aims: In last few decades, the prevalence of diabetes and vascular diseases has intensified concurrently with increased use of synthetic chemicals in agriculture. This study is aimed to evaluate the association of co-accumulation of arsenic and organophosphate (OP) insecticides with diabetes and atherosclerosis prevalence in a rural Indian population. Methods: This study included observations from KMCH-NNCD-I (2015) cross-sectional study (n = 865) from an Indian farming village. The participants had assessment of clinical parameters including HbA1c and carotid intima–media thickness and urinary heavy metals. Serum OP residues were extracted and quantified by GC–MS. Statistical analyses were performed to unravel the co-association of arsenic and OPs on prevalence of diabetes and atherosclerosis. Results: On multivariate regression analyses, total organophosphate level and arsenic accumulation showed association with diabetes and atherosclerosis. Higher odds ratio with significant trends were observed for the sub-quartiles formed by the combination of higher quartiles of arsenic and total organophosphates in association with diabetes and atherosclerosis. Conclusions: We observed evidence of possible synergism between arsenic and OPs in association with prevalence of diabetes, pre-diabetes and atherosclerosis in the study population. Our findings highlight the importance of understanding health effects of mixed exposures and raises vital questions on the role of these agrochemicals in the etiology of diabetes and vascular diseases. © 2020, Springer-Verlag Italia S.r.l., part of Springer Nature.