Background Arteriolosclerotic cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia, yet no disease‐modifying therapies exist. Anti‐inflammatory strategies targeting IL‐6 (interleukin‐6) signaling have shown efficacy in preventing atherosclerotic cardiovascular disease, but their potential in arteriolosclerotic cSVD remains unexplored. We investigated whether genetically downregulated IL‐6 signaling is associated with clinical, imaging, and pathological manifestations of arteriolosclerotic cSVD. Methods We applied 2‐sample Mendelian randomization using (1) 26 genetic variants near IL6R (interleukin‐6 receptor) associated with circulating C‐reactive protein levels and (2) rs2228145, a well‐characterized IL6R missense variant, as proxies of IL‐6 signaling downregulation. Outcomes included clinical (small vessel stroke, magnetic resonance imaging‐defined lacunar stroke, nonlobar intracerebral hemorrhage, vascular dementia), imaging (white matter hyperintensity volume, extensive basal ganglia perivascular space, nonlobar/mixed cerebral microbleeds), and pathological (arteriolosclerosis burden in autopsy) traits of cSVD, as well as atherosclerosis traits (ultrasound‐defined carotid plaque, large artery stroke) as positive controls. We used inverse‐variance weighting and the Wald ratio estimator for primary analyses. Mendelian randomization‐Egger regression, weighted median, and weighted mode estimators were used as sensitivity analyses. Results Genetically downregulated IL‐6 signaling (30% decrement in C‐reactive protein via 26 IL6R variants) was not associated with small vessel stroke (odds ratio [OR], 1.02 [95% CI, 0.95–1.10]), magnetic resonance imaging‐confirmed lacunar stroke (OR, 0.95, [95% CI, 0.81–1.11]), nonlobar intracerebral hemorrhage (OR, 1.04 [95% CI, 0.72–1.50]), or vascular dementia (OR, 1.09 [95% CI, 0.95–1.25]). Similarly, we found no significant association with cSVD imaging biomarkers or pathology‐defined arteriolosclerosis. As expected, genetically downregulated IL‐6 signaling was associated with lower odds of large artery stroke (OR, 0.79 [95% CI, 0.74–0.84]) and carotid plaque (OR, 0.88 [95% CI, 0.83–0.94]). Results were consistent across sensitivity analyses and when using the rs2228145 missense variant to proxy IL‐6 signaling downregulation. Conclusions Unlike atherosclerotic traits, genetically proxied IL‐6 signaling downregulation is not associated with clinical, imaging, or pathological manifestations of arteriolosclerotic cSVD. These genetic findings suggest that targeting IL‐6 signaling is unlikely to yield effects on cSVD prevention comparable with those expected for atherosclerotic disease.