Combination therapy has been identified as a promising strategy to improve stroke management. We conducted a systematic review and meta-analysis of evidence from animal models of ischemic stroke to determine whether combining treatments improved efficacy. Multiple databases were searched and data were extracted from focal ischemia experiments comparing control groups, single treatments, and combination treatments. Of 11,430 papers identified, 142 met the inclusion criteria; these tested 126 treatments in 373 experiments using 8,037 animals (I(2)=85 to 96%). Taken together, single treatments reduced infarct size by 20% and improved neurological score by 12% compared with control; a second therapy improved efficacy by an additional 18% and 25%, respectively. Publication bias may affect combination efficacy for infarct size but not neurological score. Combining thrombolysis with other therapies may extend the time window from 4.4 to 8 hours in animal models, although testing beyond 6 hours is required to confirm this. Benefits of additional therapy decreased as the efficacy of the primary treatment increased, with combination efficacy reaching a ceiling at 60% to 80% protection. Combining treatments may bring benefits and extend the time window for treatment. More evidence is needed due to potential publication bias and heterogeneity.