Objective To explore the correlation between DL-3-n-butylphthalide (NBP) and early neurological deterioration (END) after cerebral infarction in real-world study. Methods A multicenter registry observational study was conducted, enrolling patients with acute cerebral infarction within 72 h of onset from five hospitals in Deyang from March 31st, 2019, to July 31st, 2021. The patients were divided into two groups based on the treatment regimen, whether they received NBP in addition to standard therapy or not. The primary endpoint was END after cerebral infarction, and the secondary endpoint was unfavorable outcome (defined as modified Rankin Scale score of 3 to 6) 90 d after onset. Results A total of 314 patients with cerebral infarction were included in the study, among whom, 126 received standard therapy without NBP treatment (standard treatment group) and 188 received NBP in addition to standard therapy (NBP treatment group). A total of 69 cases occurred END within 10 d after admission. In the NBP treatment group, 32 cases (17.0%) had END within 10 d after admission, while in the standard treatment group, 37 cases (29.4%) occurred END, and the difference between the two groups was statistically significant (P=0.010). Logistic regression analyses showed that the influencing factors related to END included the serum neurofilament light chain level on admission [odds ratio (OR)=1.020, 95% confidence interval (CI) (1.004, 1.035), P=0.013], NBP treatment [OR=0.449, 95%CI (0.253, 0.797), P=0.006], and dual antiplatelet therapy [OR=0.373, 95%CI (0.196, 0.710), P=0.003], and the influencing factors for poor neurological functional prognosis in patients with cerebral infarction included age [OR=1.063, 95%CI (1.024, 1.103), P=0.002], National Institute of Health Stroke Scale score on admission [OR=1.532, 95%CI (1.313, 1.787), P<0.001], NBP treatment [OR=0.375, 95%CI (0.177, 0.794), P=0.010], and END [OR=7.450, 95%CI (3.294, 16.852), P<0.001]. Conclusion The results of our study provide the initial evidence that NBP treatment reduces the occurrence of END, and improves the neurological functional prognosis 90 d after onset in the real world.