Introduction: Thrombolysis in acute ischemic stroke (AIS) using Tenecteplase (TNK) is gaining popularity compared to Alteplase (ALT) for its practical advantages. At our center, we observed an improvement in clinical outcome in TNK treated patients compared to ALT. Hence, we aimed to study the pro-inflammatory and procoagulant responses post-thrombolysis and their contributory role in clinical outcome. Methods: This is a single-center retrospective study of ALT or TNK treated AIS patients admitted to a comprehensive stroke center over a 3-year period. Non-parametric tests were used to compare differences between the ALT and TNK cohorts. Peripheral blood indices, including neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), and mean platelet volume to platelet count ratio (MPV:PLT), were calculated. Their rise from pre-thrombolysis baseline during the first 48 hours was used to define a systemic inflammatory and procoagulant response. A p-value of <0.05 was considered statistically significant. Results: During the study period, 165 and 64 patients were treated with ALT and TNK respectively. The baseline demographics, vascular risk factors, and admission stroke severity were similar. Admission NLR, PLR, MLR, and MPV:PLT were not statistically different. Clinical outcome at 3 months assessed using median modified Rankin Scale (mRS) was better with TNK (2.0 [IQR, 1.0, 4.0] vs 3.0 [IQR, 2.0, 5.0]; p = 0.0007). Rise in NLR was significantly higher in the ALT cohort compared to TNK on day 1 (2.25 [IQR, 0.0, 5.77] vs. 0.49 [IQR, -0.48, 3.91], p = 0.01) and day 2 (1.58 [IQR, -0.09, 5.68] vs. 0.39 [IQR, -0.96, 2.91], p = 0.045). Similarly, MLR on day 2 in the ALT cohort (0.16 [IQR, 0.05, 0.49] vs. 0.12 [IQR, -0.05, 0.22], p = 0.038) and MPV:PLT on day 1 (0.61 [IQR, 0.16, 1.35] vs. 0.32 [IQR, 0.003, 0.68], p = 0.002) and day 2 (0.83 [IQR, -0.35, 1.90] vs. 0.36 [IQR, -0.12, 1.21], p = 0.004) were higher. Conclusions: Patients treated with TNK had better mRS scores compared to ALT in our study. This was associated with significantly less inflammatory and procoagulant response during the first 48 hours of AIS in the TNK group. The etiology for such an association is speculative and needs confirmation using more specific biomarkers.