(1) Background: Little is known about how left ventricular systolic dysfunction (LVSD) affects functional and clinical outcomes in acute ischemic stroke (AIS) patients undergoing thrombolysis; (2) Methods: A retrospective observational study conducted between 2006 and 2018 included 937 consecutive AIS patients undergoing thrombolysis. LVSD was defined as left ventricular ejection fraction (LVEF) < 50%. Univariate and multivariate binary logistic regression analysis was performed for demographic characteristics. Ordinal shift regression was used for functional modified Rankin Scale (mRS) outcome at 3 months. Survival analysis of mortality, heart failure (HF) admission, myocardial infarction (MI) and stroke/transient ischemic attack (TIA) was evaluated with a Cox-proportional hazards model; (3) Results: LVSD patients in comparison with LVEF ≥ 50% patients accounted for 190 and 747 patients, respectively. LVSD patients had more comorbidities including diabetes mellitus (100 (52.6%) vs. 280 (37.5%),p< 0.001), atrial fibrillation (69 (36.3%) vs. 212 (28.4%),p= 0.033), ischemic heart disease (130 (68.4%) vs. 145 (19.4%),p< 0.001) and HF (150 (78.9%) vs. 46 (6.2%),p< 0.001). LVSD was associated with worse functional mRS outcomes at 3 months (adjusted OR 1.41, 95% CI 1.03–1.92,p= 0.030). Survival analysis identified LVSD to significantly predict all-cause mortality (adjusted HR [aHR] 3.38, 95% CI 1.74–6.54,p< 0.001), subsequent HF admission (aHR 4.23, 95% CI 2.17–8.26,p< 0.001) and MI (aHR 2.49, 95% CI 1.44–4.32,p= 0.001). LVSD did not predict recurrent stroke/TIA (aHR 1.15, 95% CI 0.77–1.72,p= 0.496); (4) Conclusions: LVSD in AIS patients undergoing thrombolysis was associated with increased all-cause mortality, subsequent HF admission, subsequent MI and poorer functional outcomes, highlighting a need to optimize LVEF.