Evidence-based interventions hold promise for reducing gaps in health equity across diverse populations, but evidence about effectiveness within these populations lags behind the mainstream, often leaving opportunities to fulfill this promise unrealized. Mismatch between standard intervention outcomes research methods and the cultural and community contexts of populations at greatest risk presents additional challenges in designing and implementing rigorous studies; these challenges too often impede efforts to generate needed evidence. We draw on experiences with American Indian and Alaska Native communities to illustrate how consideration of culture and context can constructively shape intervention research and improve the quality of evidence produced. Case examples from a partnership with one American Indian community highlight opportunities for increasing alignment in intervention development, research design, and study implementation to maximize both validity and feasibility. We suggest that responsively tailoring intervention outcomes research to cultural and community contexts is fundamental to supporting health equity.