Introduction: Over 60% of premature infants are born in Africa or South Asia. Infants born early, small or who become sick after birth have a higher risk of death, poor growth and developmental impairments. Innovative interventions tailored for low- and middle-income countries are essential to help these newborns survive and develop optimally. This study evaluated the feasibility, acceptability and preliminary effectiveness of Hospital to Home (H2H), a discharge and follow-up programme for small and sick newborns in rural Uganda. Methods: We compared two cohorts of high-risk hospitalised neonates in Uganda: a historical-comparison cohort receiving standard facility-based care and an intervention cohort that received the H2H programme, a hospital and community spanning package of interventions designed to improve neurodevelopmental outcomes. We compared 6-month corrected neurodevelopmental, growth, nutritional and vaccination outcomes between the cohorts complemented by qualitative interviews of caregivers, community health workers and health facility staff. Results: We recruited 191 participants: 91 historical-comparison cohort (born between July and September 2018), and 100 intervention cohort (born July 2019 to February 2020). No statistically significant difference was seen in neurodevelopmental outcomes (adjusted OR 0.68; 95% CI: 0.32 to 1.46). Improved vaccination completion (88.5% intervention vs 76.9% comparison, p=0.041), and exclusive breastfeeding rates (42% vs 6.6%, p<0.001) were seen. Caregivers and healthcare workers reported the intervention to be acceptable and feasible in this rural Ugandan setting. Conclusion: The H2H programme was feasible and acceptable to caregivers and healthcare providers. Improved vaccination and exclusive breastfeeding rates were seen in the intervention group when compared with a historical comparison cohort in this rural Ugandan setting. Further investigation on the short and long-term effectiveness of the H2H programme in a government health services setting is warranted.