Background <p>Multiple sclerosis (MS) exhibits heterogeneity in disease courses. Although HLA DRB1*15:01 represents the strongest genetic risk factor for MS susceptibility, conferring approximately threefold increased risk, whether this allele similarly influences disease progression remains contentious.</p> Methods <p>This systematic review was conducted to clarify the relationship between HLA polymorphisms and the course of multiple sclerosis from inception through November 2025. A three-level random effects meta-analysis was used to account for statistical non-independence. Study quality was evaluated using Q GENIE criteria.</p> Results <p>In total, 56 eligible studies were selected, comprising 22,145 participants; 35 studies contributed 276 effect sizes to quantitative synthesis. The pooled estimate indicated a modest overall association between HLA variants and MS progression (Odds Ratio (OR) 1.30, 95% CI 1.09 to 1.55, <i>p</i> = 0.003). HLA DRB1*15 showed no significant association with disease progression (OR 1.10, 95% CI 0.79 to 1.51, <i>p</i> = 0.57). Exploratory subgroup analysis revealed significant regional heterogeneity (QM = 10.48, <i>p</i> = 0.033): Asian (OR 1.70, <i>p</i> &lt; 0.001) and North American (OR 1.95, <i>p</i> &lt; 0.001) studies suggested significant effects, whereas European studies showed no effect (OR 1.02, <i>p</i> = 0.92). Three alleles demonstrated significant adverse associations: HLA DRB1*04 (OR 1.79, 95% CI 1.33 to 2.42), HLA DRB1*09 (OR 4.21, 95% CI 1.93 to 9.18), and HLA DRB1*03 (OR 1.44, 95% CI 1.01 to 2.05).</p> Conclusion <p>This systematic review suggests that multiple sclerosis susceptibility and progression appear governed by distinct genetic architectures.</p>