BACKGROUND: Neonatal integrative developmental care model (NIDCM) is a holistic model of premature baby care referring to seven basic neuroprotective developmental cares (DCs) by involving the family. AIM: This study aimed to assess the effect of the application of NIDCM on the stress response of premature babies. METHODS: The research design used was quasi-experimental with a non-equivalent control group pre- and post-test. The study was conducted in the neonatal care room of Dr. Wahidin Sudirohusodo Makassar Hospital from January 2020 to April 2021. The sample was 76 subjects consisting of 38 premature babies (19 controls and 19 interventions) and 38 mothers (19 controls and 19 interventions). The collected samples were taken to the Medical Research Laboratory of Universitas Hasanuddin (HUMRC) for testing. Furthermore, baby stress was assessed from salivary cortisol levels by enzyme linked immunosorbent assay. In addition, the effect of initial cortisol, final cortisol, and birth weight on changes in salivary cortisol in premature babies was determined using the Chi-square test. RESULTS: Neither NIDCM intervention nor routine DC has been shown to descriptive statistically decrease the stress response of premature babies in the neonatal care room, some of which are even increased. However, specifically in premature babies with a birth weight of <1800 g, NIDCM showed a better effect in lowering cortisol after treatment than regular DC. CONCLUSIONS: The application of NIDCM intervention reduces the stressor felt by the babies in the neonatal care room, besides the condition of babies with a birth weight of fewer than 1800 g needs special attention with the NIDCM intervention.