Background: Cardiometabolic comorbidities are common in multiple sclerosis (MS), and lifestyle interventions are effective in managing these conditions in the general population, though evidence in the MS patient population is limited. Objective: To evaluate the effect of a multimodal lifestyle intervention on serum apolipoproteins (Apo), creatine kinase (CK), glucose, and insulin in people with progressive MS (PwPMS). Methods: This study included n = 19 PwPMS who participated in a 12-month multimodal lifestyle intervention (including a modified Paleolithic diet, exercise, neuromuscular electrical stimulation, supplements, and stress reduction). Lipid profile (ApoA1, B, and E), CK, glucose, and insulin were obtained at baseline and after 12 months under fasting conditions. Results: At 12 months, there was a marginally significant decrease in ApoB (mean change: −7.17 mg/dL; 95% CI: −14.4, 0.12; p = 0.06), while no significant changes were observed for ApoA1 (mean change: −1.28 mg/dL; 95% CI: 12.33, 9.76; p = 0.80), ApoE (mean change: +0.12 mg/dL; 95% CI: −0.27, 0.52; p = 0.51), CK (mean change: +13.19 U/L; 95% CI: −32.72, 59.11; p = 0.55), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (mean change: −0.44; 95% CI: −1.11, 0.22; p = 0.17), and HOMA-β (mean change: +45.62; 95% CI: −95.6, 186.9; p = 0.50). A positive association was observed between changes in HOMA-IR and fatigue changes at 12 months (β = 0.81, p = 0.02), suggesting that an increase in HOMA-IR was linked to increased fatigue, which was no longer significant following the exclusion of outliers (β = 0.71, p = 0.16). Conclusions: A multimodal lifestyle intervention did not negatively impact glycemic and lipid profiles. While improvements were observed in serum biomarkers, these changes were not statistically significant, highlighting the need for stronger evidence from larger, controlled studies to confirm the cardiometabolic health benefits in PwPMS.