The Two-Eyed Seeing framework advocates viewing the world with one eye grounded in Indigenous knowledges while the other eye is grounded in Westernized knowledges. Research funding bodies have recently advocated for its use in research with Indigenous peoples, yet its interpretation and application in the literature has been inconsistent. To contribute to its maturation as a framework, this article describes the application of Two-Eyed Seeing to a community-engaged study aimed at understanding how Indigenous mothers experience using health care to meet the health needs of their infants in Hamilton, Ontario, Canada. Two-Eyed Seeing was applied to the research while applying the four R’s as suggested by Kirkness and Barnhardt’s: relevance, respect, responsibility, and reciprocity. While providing practical applications of this framework to research with Indigenous mothers and infants in an urban off-reserve setting, this article also contributes an approach to data analysis that incorporates Indigenous and Western knowledges within interpretive description methodology.