Objective To investigate the related factors and clinical features of unexplained early neurological deterioration (END) of acute ischemic stroke (AIS) patients after intravenous thrombolysis. Methods A total of 258 AIS patients, who underwent intravenous thrombolysis treatment within 4.5 h of onset and were registered continuously in Stroke Center of our hospital between Jan. 2016 and Feb. 2018, were included in this study. The unexplained END was defined as the National Institutes of Health stroke scale (NIHSS) score increasing by more than 4 within 24 h of onset compared with that before thrombolysis, with no definite mechanism by imaging examination. The baseline and clinical data were compared between the unexplained END and non-END patients. The clinical features of the AIS patients with unexplained END were analyzed. Results Among the 258 patients enrolled in this study, 243 (94.2%) had no END and 15 (5.8%) had unexplained END. Compared with the patients without END, the proportion of diabetes mellitus in the patients with unexplained END was significantly higher and the door-to-needle time (DNT) was significantly longer (χ²=6.093, P=0.048; Z=2.055, P=0.040). The NIHSS score of 15 patients with unexplained END before thrombolysis was low (5[4, 9]). The most common type of trial of Org 10172 in Acute Stroke Treatment (TOAST) classification was small artery occlusion (11 cases, 73.3%). The most common infarction sites were posterior limb of internal capsule (6 cases, 40.0%) and ventromedial pons (6 cases, 40.0%). Conclusion Diabetes mellitus and long DNT may be the risk factors of unexplained END in the patients with AIS after intravenous thrombolysis. Unexplained END usually occurs in the AIS patinets with small artery occlusion and has lower NIHSS score; the common sites of infarction are posterior limb of the internal capsule and ventromedial pons.