Background Thousands of Rohingya refugee mothers at the world’s largest refugee camp located in Bangladesh are at risk of poor mental health. Accordingly, their children are also vulnerable to delayed cognitive and physical development. Objective The aim of this study is to evaluate the effectiveness of an integrated care package in reducing the prevalence of developmental delays among children aged 1 year and improving their mothers’ mental health status. Methods This is a parallel, two-arm, single-blind, cluster randomized controlled trial (cRCT). A total of 704 mother-child dyads residing at the Kutupalong refugee camp in Cox’s Bazar, Bangladesh, will be recruited from 22 clusters with 32 mother-child dyads per cluster. In the intervention arm, an integrated early childhood development and maternal mental health package will be delivered every quarter to mothers of newborns by trained community health workers until the child is 1 year old. Our primary outcome is a reduction in the prevalence of two or more childhood developmental delays of infants aged 1 year compared to the usual treatment. The secondary outcomes include reduced stunting among children and the prevalence of maternal depression. We will also assess the cost-effectiveness of the integrated intervention, and will further explore the intervention’s acceptability and feasibility. Results At the time of submission, the study was at the stage of endpoint assessment. The data analysis started in December 2020, and the results are expected to be published after the first quarter of 2021. Conclusions This study will address the burden of childhood developmental delays and poor maternal mental health in a low-resource setting. If proven effective, the delivery of the intervention through community health workers will ensure the proposed intervention’s sustainability. Trial Registration ISRCTN Registry ISRCTN10892553; https://www.isrctn.com/ISRCTN10892553 International Registered Report Identifier (IRRID) DERR1-10.2196/25047