Background: Postpartum depression interferes with maternal engagement in interventions that are effective in improving infant social-emotional and social-communication outcomes. There is an absence of integrated interventions with demonstrated effectiveness in both reducing maternal depression and promoting parent-mediated practices that optimize infant social-emotional and social-communication competencies. Interventions targeting maternal depression are often separate from parent-mediated interventions. To address the life course needs of depressed mothers and their infants, we need brief, accessible, and integrated interventions that target both maternal depression and specific parent practices shown to improve infant social-emotional and social-communication trajectories., Objective: The aim of this study is to evaluate the efficacy of a mobile internet intervention, Mom and Baby Net, with remote coaching to improve maternal mood and promote parent practices that optimize infant social-emotional and social-communication development., Methods: This is a two-arm, randomized controlled intent-to-treat trial. Primary outcomes include maternal depression symptoms and observed parent and infant behaviors. Outcomes are measured via direct observational assessments and standardized questionnaires. The sample is being recruited from the urban core of a large southern city in the United States. Study enrollment was initiated in 2017 and concluded in 2020. Participants are biological mothers with elevated depression symptoms, aged 18 years or older, and who have custody of an infant less than 12 months of age. Exclusion criteria at the time of screening include maternal homelessness or shelter residence, inpatient mental health or substance abuse treatment, or maternal or infant treatment of a major mental or physical illness that would hinder meaningful study participation., Results: The start date of this grant-funded randomized controlled trial (RCT) was September 1, 2016. Data collection is ongoing. Following the institutional review board (IRB)-approved pilot work, the RCT was approved by the IRB on November 17, 2017. Recruitment was initiated immediately following IRB approval. Between February 15, 2018, and March 11, 2021, we successfully recruited a sample of 184 women and their infants into the RCT. The sample is predominantly African American and socioeconomically disadvantaged., Conclusions: Data collection is scheduled to be concluded in March 2022. We anticipate that relative to the attention control condition, which is focused on education around maternal depression and infant developmental milestones with matching technology and coaching structure, mothers in the Mom and Baby Net intervention will experience greater reductions in depression and gains in sensitive and responsive parent practices and that their infants will demonstrate greater gains in social-emotional and social-communication behavior., Trial Registration: ClinicalTrials.gov NCT03464630; https://clinicaltrials.gov/ct2/show/NCT03464630., International Registered Report Identifier (irrid): DERR1-10.2196/31072., (©Kathleen M Baggett, Betsy Davis, Lisa Sheeber, Katy Miller, Craig Leve, Elizabeth A Mosley, Susan H Landry, Edward G Feil. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 18.08.2021.)