Background: Globally, approximately half of the estimated 6.3 million under-5 deaths occur in the neonatal period (within the first 28 days of life) and 75% of neonatal deaths occur in the first week of life. Kenya ranks among countries with the highest number of neonatal deaths, with a neonatal mortality rate of 20 per 1000 live births. Novel strategies are needed to meet the WHO’s Every Newborn Action Plan target of 10 or fewer neonatal deaths per 1000 live births by 2035. Improved identification and management of neonates with potentially life-threatening illness is critical. We developed an interactive (two-way) human-computer hybrid SMS intervention, Mobile Solutions for Neonatal Health (Mobile WACh NEO), focused on the perinatal period when risk to mothers and infants is highest. Mobile WACh NEO sends automated tailored and personalized SMS messages to mothers during pregnancy and up to 6 weeks postpartum. Messages employ the Information-Motivation-Behavior Skills (IMB) behavioral theory framework to promote 1) maternal implementation of essential newborn care (ENC, which includes early breastfeeding, exclusive breastfeeding, cord care and thermal care), 2) maternal identification of neonatal danger signs and care-seeking, and 3) maternal social support and self-efficacy. Participants can also send SMS to the study nurse, enabling on-demand remote support.Methods: We describe a two-arm unblinded randomized controlled trial (RCT) of the Mobile WACh NEO SMS intervention. The RCT will enroll 5000 third trimester pregnant women in 4 facilities in Kenya and randomize them 1:1 to receive interactive SMS communication or no SMS (control), and conduct follow-up study visits at 2 and 6 weeks postpartum. Neonatal mortality will be compared between arms as the primary outcome. Secondary outcomes include care-seeking, practice of ENC, and psychosocial health. Exploratory analysis will investigate associations between maternal mental health, practice of ENC, care-seeking and SMS engagement.Discussion: This study will contribute evidence on the impact of two-way SMS in a low-income setting on neonatal outcomes, using a rigorous evaluation design. This study will build evidence to fill a gap in understanding drivers of neonatal outcomes and the potential impact of SMS interventions.Trial registrationTrial registration: clinicaltrials.gov, NCT04598165. Registered October 22, 2020 – retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT04598165.