Objective The Thrive by Five app promotes positive interactions between children and parents, extended family, and trusted community members that support optimal socio-emotional and cognitive development in the early years. This article aims to describe the protocol for a prospective mixed-methods multi-site study evaluating Thrive by Five using surveys, interviews, workshops, audio diaries from citizen ethnographers and app usage data. Methods The study activities and timelines differ by site, with an extensive longitudinal evaluation being conducted at two sites and a basic evaluation being conducted at five sites. The learnings from the more comprehensive evaluations inform the iterative research and development processes while also ensuring ongoing evaluation of usability, acceptability and effectiveness of the app and its content across varying contexts. The study evaluates: (1) the impact of the Thrive by Five content on caregiver knowledge, behaviours, attitudes and confidence; (2) how the content changes relationships at the familial, community and system level; (3) how cultural and contextual factors influence content engagement and effectiveness and (4) the processes that facilitate or disrupt the success of the implementation and dissemination. Results All in-country partners have been identified and data collection has been completed in Indonesia, Malaysia, Afghanistan, Kyrgyzstan, Uzbekistan, Namibia and Cameroon. Conclusions Very few digital health solutions have been trialled for usability and effectiveness in diverse cultural contexts. By combining quantitative, qualitative, process and ethnographic methodologies, this innovative study informs the iterative and ongoing optimisation of the cultural and contextual sensitivity of the Thrive by Five content and the processes supporting implementation and dissemination.