Neuroinflammation plays an essential role in the process of acute ischemic stroke (AIS) injury repair. The current study seeks to investigate the relationship between the neutrophil/lymphocyte ratio (NLR) and neutrophil/high-density lipoprotein cholesterol ratio (NHR) and AIS disease severity and short-term prognosis. As such, the primary aim of this study is to improve AIS diagnosis and treatment. A total of 136 patients with AIS at the Nantong Third People’s Hospital were retrospectively analyzed. The inclusion criteria comprised patients with ischemic stroke admitted to the hospital <24 hours after symptom onset. Baseline, clinical, and laboratory data were collected from all patients within 24 hours of admission. Univariate, multivariate and receiver operating characteristic curve analysis were performed to determine the relationship between NLR, NHR, AIS severity, and short-term prognosis. NLR (odds ratio [OR] = 1.448, 95% confidence interval [CI] 1.116–1.878,P= .005) and NHR (OR = 1.480, 95% CI 1.158–1.892,P= .002) were identified as independent risk factors for stroke severity. Additionally, the correlation between combined NLR and NHR and AIS severity achieved a sensitivity of 81.4% and specificity of 60.4% with a best cutoff value of 6.989. This outcome was superior to that of the single composite inflammatory index. Moreover, NLR (OR = 1.252, 95% CI 1.008–1.554,P= .042) was an independent risk factor for poor short-term prognosis in patients with AIS. When the optimal cutoff value was 2.605, the sensitivity of NLR correlation with the short-term prognosis of AIS was 82.2%, and the specificity was 59.3%. NLR combined with NHR exhibits a strong correlation with disease severity in AIS. Meanwhile, an elevated NLR in patients with AIS can predict a poor short-term prognosis.