The therapeutic outcomes for acute ischemic stroke (AIS) with early neurological deterioration (END) are adverse. Argatroban is a novel direct thrombin inhibitor, which is safe in the treatment of AIS, but its efficacy is controversial. This study sought to assess the therapeutic effect of argatroban as an adjunct to aspirin in the treatment of AIS patients with END. Patients' prognosis for the presence of END was also evaluated. Overall, 166 AIS patients with END were included in the study from June 2018 to June 2021 in The Affiliated Zhangjiagang Hospital of Soochow University. Patients were divided in the control group (aspirin alone) and the study group (aspirin combined with argatroban). General data of the patients were collected. Clinical indexes such as the modified Edinburgh-Scandinavian stroke scale (MESSS), and the serum fibrinogen (FIB) and neuropeptide Y (NPY) levels before and after treatment were also collected. Correlations between prognosis and general data, and FIB and NPY levels in AIS patients with END were analyzed by multivariate logistic regression. The performance of FIB and NPY levels in predicting patients' prognosis was further analyzed using receiver operating characteristic (ROC) curves. There was no significant difference in the general data, such as sex, age, course of disease and basic diseases between the 2 groups. After treatment, the MESSS score (13.08 ± 3.24 vs. 16.48 ± 3.32, p < 0.001), serum FIB level (2.72 ± 0.81 vs. 3.52 ± 0.71, p < 0.001), and NPY level (121.28 ± 17.34 vs. 152.09 ± 18.25, p < 0.001) of the study group was significantly lower than that of the control group. A further analysis revealed that the serum FIB (OR, odds ratio = 2.296, 95% confidence interval, CI: 1.437-3.669, p = 0.001) and NPY (OR = 1.020, 95% CI: 1.002-1.039, p = 0.031) levels were independent risk factors of patients' prognosis for the presence of END. Aspirin combined with argatroban significantly improved neurological impairment of AIS patients with END, which is worthy of clinical application.