In previous studies, prothrombin time (PT), systemic inflammation response index (SIRI) and systemic immune inflammation Index (SII) levels might be the prognostic factors for patients with ischemic stroke. However, the association between these coagulation and inflammation biomarkers and prognosis in patients with acute ischemic stroke (AIS) who undergo intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) remains unclear and needs further study. Thus, this study aimed to investigate the relationship between these biomarkers and clinical prognosis after IVT in AIS patients. We included patients at the Hebei general hospital diagnosed with AIS who received standard-dose IVT with rt-PA from September 2017 to August 2022. Demographic information, vascular risk factors, laboratory test results, and other stroke-related data were collected for analysis. Clinical outcomes included short-term outcome at 24 h and functional outcome at 3 months. We enrolled 281 patients in this study. In total, 16 patients had END within 24 h, and 106 patients had an unfavorable outcome at the 3-month visit. In the multivariate analysis, PT level (OR = 1.833; 95% CI: 1.161-2.893; P = 0.009), SIRI level (OR = 2.166; 95% CI: 1.014-4.629; P = 0.046) and SII level (OR = 1.002; 95% CI: 1.000-1.003; P = 0.021) were independently associated with 3-month poor outcome in AIS patients with IVT. In conclusion, the higher PT, SIRI and SII levels were independently associated with poor prognosis in AIS patients after IVT. Additionally, PT, SIRI and SII all can be novel short-term prognostic biomarkers for AIS patients treated with IVT.