Background: Care for women and babies before, during, and after the time of birth is a sensitive measure of the functionality of any health system. Engaging communities in preventing newborn deaths is a promising strategy to achieve further progress in child survival in sub-Saharan Africa. Objective: To assess the effect of a home visit strategy combined with health facility strengthening on uptake of newborn care-seeking, practices and services, and to link the results to national policy and scale-up in Uganda. Design: The Uganda Newborn Study (UNEST) was a two-arm cluster-randomised controlled trial in rural eastern Uganda. In intervention villages volunteer community health workers (CHWs) were trained to identify pregnant women and make five home visits (two during pregnancy and three in the first week after birth) to offer preventive and promotive care and counselling, with extra visits for sick and small newborns to assess and refer. Health facility strengthening was done in all facilities to improve quality of care. Primary outcomes were coverage of key essential newborn care behaviours (breastfeeding, thermal care, and cord care). Analyses were by intention to treat. This study is registered as a clinical trial, number ISRCTN50321130. Results: The intervention significantly improved essential newborn care practices, although many interventions saw major increases in both arms over the study period. Immediate breastfeeding after birth and exclusive breastfeeding were significantly higher in the intervention arm compared to the control arm (72.6% vs. 66.0%; p = 0.016 and 81.8% vs. 75.9%, p = 0.042, respectively). Skin-to-skin care immediately after birth and cord cutting with a clean instrument were marginally higher in the intervention arm versus the control arm (80.7% vs. 72.2%; p = 0.071 and 88.1% vs. 84.4%; p = 0.023, respectively). Half (49.6%) of the mothers in the intervention arm waited more than 24 hours to bathe the baby, compared to 35.5% in the control arm (p < 0.001). Dry umbilical cord care was also significantly higher in intervention areas (63.9% vs. 53.1%, p < 0.001). There was no difference in care-seeking for newborn illness, which was high (around 95%) in both arms. Skilled attendance at delivery increased in both the intervention (by 21%) and control arms (by 19%) between baseline and endline, but there was no significant difference in coverage across arms at endline (79.6% vs. 78.9%; p = 0.717). Home visits were pro-poor, with more women in the poorest quintile visited by a CHW compared to families in the least poor quintile, and more women who delivered at home visited by a CHWafter birth (73.6%) compared to those who delivered in a hospital or health facility (59.7%) (p < 0.001). CHWs visited 62.8% of women and newborns in the first week after birth, with 40.2% receiving a visit on the critical first day of life. Conclusions: Consistent with results from other community newborn care studies, volunteer CHWs can be effective in changing long-standing practices around newborn care. The home visit strategy may provide greater benefit to poorer families. However, CHW strategies require strong linkages with and concurrent improvement of quality through health system strengthening, especially in settings with high and increasing demand for facility-based services.