Insulin resistance (IR) is a key pathogenic mechanism underlying numerous cardiometabolic disorders. While sociodemographic and lifestyle determinants of IR are well-established, their association with health-related quality of life (HRQoL) remains understudied. This study explores the relationship between IR risk, as measured by TyG, METS-IR, and SPISE-IR indices, and HRQoL in a large cohort of Spanish workers. This cross-sectional study included 100,014 Spanish workers aged 18-69 years evaluated between January 2021 and December 2023. Exclusion criteria included incomplete clinical, laboratory, or questionnaire data. IR was assessed using TyG, METS-IR, and SPISE-IR indices. HRQoL was measured using the SF-12 questionnaire. Sociodemographic factors, physical activity (IPAQ), dietary habits (MEDAS-14), and social class (based on CNAE-11 and Spanish Society of Epidemiology criteria) were also evaluated. Statistical analysis was conducted using SPSS v29.0. Higher IR risk was consistently associated with older age, male sex, lower social class, current smoking, low adherence to the Mediterranean diet, and physical inactivity. Lower HRQoL scores (both physical and mental components) were significantly associated with higher IR indices, particularly with METS-IR and SPISE-IR. These associations persisted after adjusting for sociodemographic and behavioral covariates. This study demonstrates a robust association between insulin resistance risk and diminished health-related quality of life. The integration of validated IR indices and subjective health perception tools such as the SF-12 may enhance early identification of at-risk individuals in occupational health settings.