Objective To investigate the risk factors for early neurological deterioration (END) following intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) acute mild ischemic stroke (AMIS) patients. Methods Eighty-six patients with AMIS who underwent intravenous thrombolysis with rt-PA in the Department of Neurology, Civil Aviation General Hospital between January 2019 and October 2022 were retrospectively analyzed. Patients were categorized into END group (n=8) and non-END group (n=78) based on the presence of END within 24 hours after thrombolysis (NIHSS score increased by ≥2 points within 24 hours after intravenous thrombolysis). Baseline characteristics, including age, gender, past medical history (hypertension, diabetes, hyperlipidemia, etc.), smoking history, pre-thrombolysis NIHSS score, homocysteine level, fibrinogen level, and post-thrombolysis bleeding transformation were documented for each patient. A multivariate logistic regression analysis was conducted to access the risk factors associated with END following intravenous thrombolysis in AMIS. Results There were significant differences in homocysteine and fibrinogen levels, as well as bleeding transformation after thrombolysis between the two groups (P<0.05). In contrast, other factors such as age, gender, past medical history, pre-thrombolysis NIHSS score, and other imaging features were not statistically significant (P>0.05). Multivariate logistic regression analysis revealed that elevated homocysteine level was independently linked to risk of END after intravenous thrombolysis in AMIS, with an odds ratio of 1.074(95%CI 1.011-1.142, P=0.021). Conclusions Hyperhomocysteinemia emerges as an independent risk factor for END following intravenous thrombolysis in patients with AMIS.