<p>Monocyte-to-lymphocyte ratio (MLR) and systemic inflammation response index (SIRI) are independently associated with osteoporosis (OP) and cardiovascular disease (CVD). However, whether MLR and SIRI mediate the relationship between OP and CVD remains unknown. To investigate the linkage between OP and CVD prevalence in women and the mediating role of MLR and SIRI. Data were obtained from the NHANES. Logistic regression and restricted cubic spline analyses were used to explore the associations among OP, femoral bone mineral density (BMD), and CVD prevalence in women. Subgroup analyses were conducted to examine differences in the linkage between OP and CVD prevalence among different populations. Mediation analyses were performed to assess the mediating effects of MLR and SIRI in the aforementioned associations. Subgroup analysis evaluated association heterogeneity; mediation analysis assessed MLR and SIRI mediating effects. 2,292 participants were included. Logistic regression showed that in Model III, OP was positively linked with CVD prevalence in women (OR = 2.09, 95% CI: 1.02–4.28, P = 0.044). Furthermore, in Model III, total femur BMD (OR = 0.06, 95% CI: 0.01–0.53, P = 0.013) and intertrochanteric BMD (OR = 0.06, 95% CI: 0.01–0.39, P = 0.004) were negatively associated with CVD prevalence in women, with no evidence of non-linear associations (P-non-linear &gt; 0.05). Subgroup analysis revealed a stronger association in non-estrogen-users, women with a high school education or lower, and physically inactive women. MLR and SIRI mediated 6.27% and 5.66% of the association between OP and CVD prevalence, respectively. OP and CVD prevalence are significantly positively correlated in the female population, which is partially mediated by the systemic inflammatory markers MLR and SIRI. These findings provide new insights for cardiovascular risk management in women with OP in clinical practice.</p>