Aim To explore the predictive value of plasma soluble thrombomodulin (sTM) level for early neurological deterioration after recombinant tissue-type plasminogen activator (rt-PA) intravenous thrombolysis in patients with ischemic stroke. Methods A total of 183 patients with ischemic stroke who met the inclusion criteria were collected as the research objects. According to the degree of neurological deficit 24 hours after rt-PA intravenous thrombolysis, the patients were divided into neurological deterioration group with 31 cases and non-neurological deterioration group with 152 cases. The general clinical data were collected, such as patient age and high-sensitivity C-reactive protein (hs-CRP), the plasma sTM level was detected by enzyme-linked immunosorbent assay (ELISA); the correlation between plasma sTM and general data of ischemic stroke patients with early neurological deterioration after rt-PA intravenous thrombolysis was analyzed by Pearson's method and Spearman's method; the predictive value of plasma sTM for early neurological deterioration after rt-PA intravenous thrombolysis in patients with ischemic stroke was analyzed by receiver operating characteristic curve (ROC curve); the factors affecting early neurological deterioration after rt-PA intravenous thrombolysis in patients with ischemic stroke were analyzed by multivariate Logistic regression. Results The plasma sTM ((50.64±12.17) μg/L vs. (33.76±8.67) μg/L), age ((67.34±10.87) years vs. (60.22±11.05) years), hs-CRP ((12.59±3.23) mg/L vs. (4.92±1.13) mg/L), fasting blood glucose ((7.31±1.96) mmol/L vs. (5.86±1.92) mmol/L), and proportion of diabetes (32.26% vs. 16.45%) were higher in the neurological deterioration group than those of the non-neurological deterioration group, and the difference was statistically significant (P＜0.05). Plasma sTM of ischemic stroke patients with early neurological deterioration after rt-PA intravenous thrombolysis was positively correlated with age, hs-CRP, fasting blood glucose, and diabetes (P＜0.05). The area under the curve (AUC) of plasma sTM predicting early neurological deterioration after rt-PA intravenous thrombolysis in patients with ischemic stroke was 0.852, the specificity was 81.6%, and the sensitivity was 80.6%. sTM and fasting blood glucose were independent factors influencing early neurological deterioration after rt-PA intravenous thrombolysis in patients with ischemic stroke (P＜0.05). Conclusion Plasma sTM has important predictive value for early neurological deterioration after rt-PA intravenous thrombolysis in patients with ischemic stroke.