Background <p>High-sensitivity C-reactive protein (hs-CRP) is a well-established biomarker of systemic inflammation and endothelial dysfunction. Its role in capturing inflammatory processes underlying migraine remains unclear. We aimed to determine whether serum hs-CRP levels are associated with migraine.</p> Methods <p>This cross-sectional study enrolled adult participants with migraine and sex-matched healthy controls (HCs). Serum hs-CRP concentrations (mg/L) were measured using a validated assay. Participants with migraine were categorized into subgroups based on type (with aura, without aura, chronic, episodic) and headache status at sampling (ictal, interictal). The primary outcome was the percentage difference in serum hs-CRP concentrations between participants with migraine and HCs. Secondary outcomes included comparisons of hs-CRP levels across migraine subgroups and between each subgroup and HCs. Multivariate regression models were used to assess associations between hs-CRP and migraine after adjusting for age, sex, body mass index, and smoking status.</p> Results <p>A total of 642 participants with migraine and 154 sex-matched HCs were enrolled. Of these, 630 with migraine (565 [89.7%] females) and 153 HCs (131 [85.6%] females) provided eligible outcome data. Participants with migraine exhibited significantly higher hs-CRP concentrations than HCs, with an average increase of 31.2% (95% CI, 9.4–57.3%; <i>P</i> = 0.003). Subgroup analyses showed higher hs-CRP in migraine with aura (47.0% above HCs; <i>P</i> = 0.002) and chronic migraine (33.5% above HCs; <i>P</i> = 0.009).</p> Conclusions <p>Elevated hs-CRP levels were identified in adults with migraine, implicating low-grade inflammation in migraine pathogenesis.</p>