Abstract Background Population-based studies analyzing neonatal deaths in middle-income countries may contribute to design interventions to achieve the Sustainable Development Goals, established by United Nations. This study goal is to analyze the annual trend of neonatal mortality in São Paulo State, Brazil, over a 10-year period and its underlying causes and to identify maternal and neonatal characteristics at birth associated with neonatal mortality. Method A population-based study of births and deaths from 0 to 27 days between 2004 and 2013 in São Paulo State, Brazil, was performed. The annual trend of neonatal mortality rate according to gestational age was analyzed by Poisson or by Negative Binomial Regression models. Basic causes of neonatal death were classified according to ICD-10. Association of maternal demographic variables (block 1), prenatal and delivery care variables (block 2), and neonatal characteristics at birth (block 3) with neonatal mortality was evaluated by Poisson regression analysis adjusted by year of birth. Results Among 6,056,883 live births in São Paulo State during the study period, 48,309 died from 0 to 27 days (neonatal mortality rate: 8.0/1,000 live births). For the whole group and for infants with gestational age 22–27, 28–31, 32–36, 37–41 and ≥ 42 weeks, reduction of neonatal mortality rate was, respectively, 18 %, 15 %, 38 %, 53 %, 31 %, and 58 %. Median time until 50 % of deaths occurred was 3 days. Main basic causes of death were respiratory disorders (25 %), malformations (20 %), infections (17 %), and perinatal asphyxia (7 %). Variables independently associated with neonatal deaths were maternal schooling, prenatal care, parity, newborn sex, 1st minute Apgar, and malformations. Cesarean delivery, compared to vaginal, was protective against neonatal mortality for infants at 22–31 weeks, but it was a risk factor for those with 32–41 weeks. Conclusions Despite the significant decrease in neonatal mortality rate over the 10-year period in São Paulo State, improved access to qualified health care is needed in order to avoid preventable neonatal deaths and increase survival of infants that need more complex levels of assistance.