Background: Premature birth and infant hospitalization in the neonatal intensive care unit (NICU) is stressful for parents; therefore, training and supporting couples with the aim of reducing stress are very important. Objectives: The present study aimed at investigating the effect of family-centered educational, supportive intervention on parental stress of premature infants hospitalized in the NICU. Methods: This quasi-experimental study was performed on the eligible parents of 80 premature infants admitted to the NICU ward of Ali-ibn Abitaleb Hospital in Zahedan, in two groups of 40 intervention and control. Samples were selected by convenience sampling and randomly divided into two groups. The intervention group received five sessions of a family-centered educational support program in five days, with an average of 60 minutes per session, and the control group received only routine training and care. Data were collected using the Parental Stress scale (PSS) questionnaire with approved validity and reliability before and after the end of educational interventions at discharge from the hospital. Data were analyzed by SPSS, version 22 using paired t-test, independent t-test, and chi-square. Results: Mean of parental stress scores of mothers and fathers of premature infants was not significantly different in the intervention and control groups before family-centered educational-supportive intervention (P > 0.05), but after the intervention, the mean of parental stress scores of parents in the intervention group was significantly lower than the control group (P = 0.001). Conclusions: Family-centered educational supportive intervention has a positive and significant effect on reducing stress in parents of preterm infants admitted to NICU. Therefore, training and support of parents during the hospitalization of their infants is recommended.