Introduction: Culture-negative and multidrug-resistant neonatal sepsis frequently occur in developing countries and complicate neonatal sepsis management. These conditions contribute to a high neonatal mortality rate and accelerate the misuse of antibiotics. However, the extent of culture-negative and multidrug-resistant neonatal sepsis in developing countries remains poorly characterized. This study aims to describe culture-negative and culture-proven neonatal sepsis epidemiology and the antimicrobial resistance patterns in Palembang, Indonesia. Methodology: A retrospective review of the medical records of all neonatal admissions between January 2016 and December 2018 was conducted at a tertiary-level referral hospital in Indonesia. The maternal and neonatal characteristics and microbiological results of the identified sepsis cases were obtained and analyzed. Results: Three hundred and fifty-six neonatal sepsis cases were admitted from 2016 to 2018, accounting for 14.1% of neonatal hospital admissions. The percentages of early-onset and late-onset sepsis were comparable (49.7% vs. 50.3%), with an 18.1% case fatality rate. The proportion of culture-negative sepsis was 44%. The mortality rates between culture-proven and culture-negative sepsis cases did not differ statistically (p = 0.11). Coagulase-negative staphylococci (30.9%), Klebsiella pneumoniae (18.1%), and Acinetobacter spp. (10.7%) were the most frequently isolated pathogens. Overall, 62.6% of all isolated organisms were multidrug-resistant bacteria, with a high prevalence of extended-spectrum cephalosporin-resistant and carbapenem-resistant strains. Conclusions: Culture-negative sepsis accounts for a significant proportion of neonatal sepsis cases. Early- and late-onset and culture-negative and culture-proven neonatal sepsis contribute to a comparable proportion of neonatal sepsis morbidity and mortality. There is an alarmingly high prevalence of resistance to extended-spectrum cephalosporin and carbapenem in neonatal sepsis cases.