People in the United States and around the world are widely exposed to pyrethroid pesticides. However, little is known about the effect of pyrethroids exposure on obesity in adults. This study examined the association between pyrethroids exposure and obesity in males and females and the role of obesity in the association of pyrethroids exposure with diabetes and cardiovascular disease (CVD). We used data from the National Health and Nutrition Examination Survey 1999-2002 and 2007-2014. Multivariate linear regression and logistic regression models were fitted to assess the association between urinary 3-Phenoxybenzoic Acid (3-PBA, a validated biomarker for pyrethroids exposure used in the primary analysis) and obesity. Mediation analyses were performed to investigate the mediation role of obesity on the associations of 3-PBA with diabetes and CVD. In this analysis, 7896 participants aged 20 years and above were included, of which 1235 (32.2%) males and 1623 (39.9%) females were diagnosed as obese. There was a significant interaction between sex and 3-PBA (Pinteraction = 0.004) for the risk of obesity. Among females, participants in the highest tertile of urinary 3-PBA had higher odds of obesity (OR = 1.22, 95% CI: 1.00, 1.48) compared to those in the lowest tertile after adjusting for covariates. Among males, the association was not statistically significant. Similar trends were found in the associations of log-transformed urinary 3-PBA level with body mass index in males and females. Further, we found that, in males and females, obesity explained the effect of 3-PBA exposure on diabetes by 1.1% (P = 0.850) and 13.6% (P = 0.004), as well as cardiovascular diseases by 5.9% (P = 0.785) and 25.0% (P = 0.016), respectively. In conclusion, 3-PBA was significantly associated with a higher risk of obesity, especially in females. In addition, obesity partially mediated the associations of 3-PBA exposure with diabetes and CVD.