Abstract This study aims to investigate the relationship between the triglyceride-glucose body mass index (TyG-BMI) and cardiovascular disease (CVD) among middle-aged and elderly women, using data from the National Health and Nutrition Examination Survey (NHANES) spanning from 1999 to 2018. TyG-BMI was calculated as Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2] × BMI. After applying the sampling weights from NHANES, the study sample of 6,343 participants is representative of approximately 59,174,898 American women. We categorized TyG-BMI into quartiles, using Q3 as the reference group. In the crude model, Q4 exhibited a 40% increased odds of CVD (odds ratio [OR] = 1.40, 95% confidence interval [CI] 1.09–1.79, P = 0.009). In the fully adjusted model, the increased odds of CVD for Q4 relative to Q3 was 39% (OR = 1.39, 95% CI 1.06–1.82, P = 0.019). Further analysis using restricted cubic splines (RCS) and threshold effect analysis confirmed a nonlinear relationship between them. Below a TyG-BMI threshold of 260, there was no significant association with CVD odds. However, above 260, each 10-unit increase in TyG-BMI was associated with a 2.4% increase in CVD odds in this demographic. Sensitivity analyses confirmed the stability of the results.