Ischemic stroke (IS) is the leading cause of disability and contributes to a significant socio-economic cost in the western world. Brain repair strategies investigated in the pre-clinical models include the delivery of drug or cell-based therapeutics; which is hindered by the complex anatomy and functional organization of the brain. Biomaterials can be instrumental in alleviating some of these challenges by providing a structural support, localization, immunomodulation and/or modulating cellular cross-talk in the brain. This review addresses the significance of and challenges associated with cell therapy in an ischemic brain. This is followed by a detailed insight into the biomaterial-based delivery systems which have been designed to provide sustained trophic factor delivery for endogenous repair and to support transplanted cell survival and integration. A biomaterial intervention uses a multifaceted approach in enhancing the survival and engraftment of cells during transplantation and this has driven them as potential candidates for the treatment of IS. The biological processes that are activated as a response to the biomaterials and how to modulate them is one of the key factors contributing to the success of the biomaterial-based therapeutic approach. Future perspectives highlight the need of a combinative approach of merging the material design with disease biology to fabricate effective biomaterial-based intervention of stroke.