This study compared the effects of Mat Pilates training on cardiovascular risk markers in postmenopausal women with single or multiple cardiometabolic conditions. Forty-four women were divided into single-condition (SINGLE; n = 20) and multiple-condition (MULTI; n = 24) groups. Both groups completed Mat Pilates three times per week for 12 weeks. Measurements of resting blood pressure, body composition, dietary intake, and blood markers were taken before and after the intervention. A Generalized Estimating Equation was used for hypothesis testing. MULTI presented higher body mass, BMI, fat mass, and waist circumference. Systolic blood pressure decreased more in SINGLE (−13 ± 15 mmHg) than in MULTI (−3 ± 16 mmHg, p interaction = 0.016 with diastolic reductions in both groups (SINGLE: −9 ± 12 mmHg; MULTI: −2 ± 11 mmHg, p interaction = 0.053). Triglycerides decreased only in SINGLE (−40 ± 98 mg/dL vs. +31 ± 70 mg/dL in MULTI, p interaction = 0.006), while no significant changes were observed in cholesterol levels. Adiponectin levels decreased in both groups (SINGLE: −1.5 ± 16.3; MULTI: −9.3 ± 12.4 vs. µg/dL, p time = 0.015). Glycated hemoglobin levels decreased over time in both groups (−0.3 ± 0.5% in SINGLE, −0.5 ± 0.6% in MULTI, p time < 0.001), with no significant changes in blood glucose. These findings suggest that Mat Pilates may be more effective in reducing cardiometabolic risk factors in women with a single condition compared to those with multiple conditions.