Infection is the major cause of neonatal deaths. Home born newborns in rural Bangladeshi communities are exposed to environmental factors increasing their vulnerability to a number of disease agents that may compromise their health. The current analysis was conducted to assess the association of very severe disease (VSD) in newborns in rural communities with temperature, rainfall, and humidity. A total of 12,836 newborns from rural Sylhet and Mirzapur communities were assessed by trained community health workers using a sign based algorithm. Records of temperature, humidity, and rainfall were collected from the nearest meteorological stations. Associations between VSD and environmental factors were estimated. Incidence of VSD was found to be associated with higher temperatures (odds ratios: 1.14, 95% CI: 1.08 to 1.21 in Sylhet and 1.06, 95% CI: 1.04 to 1.07 in Mirzapur) and heat humidity index (odds ratios: 1.06, 95% CI: 1.04 to 1.08 in Sylhet and, 1.03, 95% CI: 1.01 to 1.04 in Mirzapur). F our months (June-September) in Sylhet, and six months in Mirzapur (April-September) had higher odds ratios of incidence of VSD as compared to the remainder of the year (odds ratios: 1.72, 95% CI: 1.32 to 2.23 in Sylhet and, 1.62, 95% CI: 1.33 to 1.96 in Mirzapur). Prevention of VSD in neonates can be enhanced if these interactions are considered in health intervention strategies.