BACKGROUND AND PURPOSE To assess the effect of acute thrombolysis protocol on "door-to-needle time" (DTN) and improvement in outcome following acute stroke (AS). METHODS The charts of all patients receiving intravenous (IV) thrombolysis for AS between January 2008 and June 2015 were reviewed for DTN, complications, and clinical outcome. Good prognosis was defined as modified Rankin Scale (mRS) score of less than 2 at 90 days. In January 2014, a protocol for faster DTN was introduced. We reviewed the prognosis before and after the introduction of the new protocol. RESULTS Up to 204 patients received IV recombinant tissue plasminogen activator (r-tPA) (mean age 52.5 ± 12.4 years). Mean door-to-CT time improved from 42.5 ± 41.1 to 27.1 ± 26.3 minutes (P < .001); DTN improved from 83.26 ± 47.7 to 47.09 ± 25.7 minutes (P < .001). Complications were reduced from 15.7% to 8.8% (P = .14). The mRS score of less than or equal to 2 improved from 47.1% to 73.3% at 90 days (P = .001). After implementing new protocol, thrombolysis rate increased to 11.8% in 2014 (before 3.3% in 2011, 4.9% in 2012, and 4.4% in 2013), P < .0001. NIHSS (National Institutes of Health Stroke Scale) score at admission (P = .002), hypodensity on initial CT brain (P = .041), protocol implementation (P = .014), and reduced length of stay (P = .004) were associated with outcome at 90 days (mRS score ≤2). CONCLUSION Implementation of specific protocols to reduce DTN in patients receiving IV r-tPA leads to reduction in complications and improves outcome.