Stem cell treatment is emerging as an appealing alternative for stroke patients, but there still needs to be an agreement on the protocols in place, including the route of administration. This systematic review aimed to assess the efficacy and safety of the administration routes of stem cell treatment for ischemic stroke. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A comprehensive literature search was undertaken using the PubMed, Scopus, and Cochrane databases. A total of 21 publications on stem cell therapy for ischemic stroke were included. Efficacy outcomes were measured using the National Institutes of Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and the Barthel index (BI). Intracerebral administration showed a better outcome than other routes, but a greater number of adverse events followed due to its invasiveness. Adverse events were shown to be related to the natural history of stroke not to the treatment. However, further investigation is required, since studies have yet to compare the different administration methods directly.