Background: Low birth weight (LBW), defined as a birth weight of less than 2500 grams, remains a significant public health issue globally. The prevalence and determinants of LBW can vary based on geographic location, socioeconomic status, maternal health, and access to healthcare facilities. In Khyber Pakhtunkhwa (KP), a province in Pakistan with varying rural and urban populations, understanding the regional disparities in LBW prevalence and its contributing factors is crucial for targeted interventions. Objective: To assess the prevalence and determinants of LBW among newborns in rural and urban regions of Khyber Pakhtunkhwa. Methods: This study employed a cross-sectional design, using a sample of 1000 newborns from both rural and urban areas of KP from January 2022 to September 2024. Data was collected from hospitals and healthcare centers in the regions of urban and rural, both representative of their respective areas in terms of demographics and healthcare accessibility. Inclusion criteria included all newborns born during the study period, with a documented birth weight recorded within 24 hours of birth. Exclusion criteria included newborns with congenital anomalies, twin pregnancies, or those born to mothers with pre-existing conditions such as diabetes or hypertension. Data was collected using a structured questionnaire administered to mothers. Results: The prevalence of LBW in the rural areas was significantly higher (30%) than in urban areas (18%). Maternal education, socioeconomic status, antenatal care, and maternal health were identified as significant determinants of LBW. Conclusion: The study revealed significant disparities in LBW prevalence between rural and urban regions of Khyber Pakhtunkhwa. Regional differences in healthcare access, maternal nutrition, and education majorly contribute to these disparities. Interventions focusing on improving maternal healthcare services, especially in rural areas, are recommended.