Objective To explore the relationship between neurofilament light chain (NfL) level and early neurological deterioration (END) after acute cerebral infarction (ACI). Methods The means of multi-center observational study were adopted to include patients with ACI within 72 hours of onset in 4 hospitals in Deyang between March 31, 2019 and July 31, 2021, to explore the risk factors of END. Results A total of 339 patients with ACI were included in this study, including 131 women and 208 men, aged (68.1±11.6) years. END occurred in 80 patients within 7 days after admission, and the incidence of END was 23.6%. The National Institute of Health Stroke Scale score and NfL level of patients without END were lower than those with END (P<0.05). Cox proportional risk model showed that NfL level [hazard ratio (HR)=1.037, 95% confidence interval (CI) (1.025, 1.050), P<0.001], admission National Institute of Health Stroke Scale score [HR=1.202, 95% CI (1.127, 1.282), P<0.001], initial blood glucose [HR=1.068, 95% CI (1.006, 1.133), P=0.030] were related to the occurrence of END. Conclusion The level of NfL, the severity of stroke, and the bloodglucose at admission are related to the occurrence of END in patients with ACI. Measures can be taken to control the above problems as soon as possible to prevent the occurrence of END.