Introduction <p>Late-onset multiple sclerosis (LOMS, onset &gt; 50&#xa0;years) is increasingly recognized and may differ from adult-onset MS (AOMS).</p> Objectives <p>To compare clinical, motor, and cognitive features of LOMS vs. AOMS, and explore the influence of fatigue and depression on cognitive impairment.</p> Methods <p>In this case–control study, 41 LOMS patients and 82 disease duration- and sex-matched AOMS patients underwent neurological evaluation (including recording of vascular risk factors), neuropsychological evaluations (including fatigue and depression), and motor function assessment (9-Hole Peg and Timed 25-Foot Walk tests). Group differences were FDR-corrected. Logistic regressions tested associations and interactions of fatigue and depression with cognitive impairment. A <i>p</i> &lt; 0.05 was considered statistically significant.</p> Results <p>Compared to AOMS, LOMS patients more frequently presented with motor onset and progressive phenotypes, had higher EDSS, higher prevalence of patients with EDSS ≥ 4, and were less often treated (pFDR ≤ 0.011). No differences emerged in vascular risk factor prevalence and motor task performance. Compared to AOMS, LOMS showed more frequent cognitive impairment (36% vs 17%), with worse performance in attention, verbal fluency, and global cognition (pFDR ≤ 0.049). LOMS patients were also more frequently fatigued (63% vs 32%) and had higher fatigue severity scores (pFDR ≤ 0.033). Depression did not differ between groups. Fatigue was associated with cognitive impairment only in LOMS (OR = 1.13, 95% confidence interval = 1.05–1.22, <i>p</i> = 0.002), with a significant group × fatigue interaction (<i>p</i> = 0.014), independent of age and disability. No association was found between depression and cognitive impairment.</p> Conclusions <p>LOMS showed a worse clinical and cognitive profile than AOMS, with fatigue playing a significant role in cognitive vulnerability.</p>