: Unhealthy lifestyles are closely linked to insulin resistance (IR) and adiposity. However, the mediating role of adiposity in the relationship between lifestyle factors and IR is not yet fully understood. Mediation analysis may help clarify the role of adiposity in the relationship between lifestyle factors and IR. Therefore, we aimed to explore the bidirectional relationship between adiposity and IR, and to evaluate the relationship between lifestyle factors and adiposity-mediated IR in Mexican adults. : A longitudinal analysis was conducted using data from the Health Workers Cohort Study, with measurements taken every six years from 2004 to 2018. This study included 1134 participants aged from 18 to 70 years. Lifestyle factors were assessed using a self-administered questionnaire. IR was assessed using the Homeostasis Model Assessment (HOMA). Adiposity was measured through body mass index (BMI), waist circumference (WC), and body fat proportion (BFP), and BMI was used as the marker indicator to set the metric of adiposity. We fitted structural equation models with a cross-lagged specification to examine the relationships between adiposity and ln(HOMA). In our analysis, we considered baseline adiposity and ln(HOMA) as mediators of the relation between lifestyle factors and future adiposity and ln(HOMA). Models were stratified by sex and adjusted by baseline age. : Results from the cross-lagged panel model showed that, for both men and women, adiposity predicted subsequent increases in HOMA (+5.3% IC95%: 1.8%, 9.0% in men; +6.0% IC95%: 4.2%, 7.8% in women). In men, baseline adiposity acted as a mediator between lifestyle variables (physical activity, tobacco consumption, and sleep duration) and HOMA. : Our results suggest that understanding both the relationship between adiposity and HOMA and the mediating effects of adiposity is crucial for developing effective interventions to reduce IR in the Mexican population.