Background: Pain management by non-pharmacological interventions in neonates is a crucial area of research. Aim: To evaluate the effect of facilitated tucking and non-nutritive sucking on pain intensity among preterm infants during heel-stick. Methods: A quasi –experimental research pre-posttest design was utilized on a purposive sample of one hundred and twenty one preterm infants from Neonatal Intensive Care Units at El Manial (Kaser Al Aini) and EL Monira Pediatric Hospitals that are affiliated to Cairo University from April 2023 to July 2024. They were allocated into four groups (control /no pain relief method, facilitated tucking, non-nutritive sucking, and facilitated tucking combined with non-nutritive sucking). Facilitated tucking, non-nutritive sucking, and facilitated tucking combined with non-nutritive sucking were compared with the routine care method (no intervention) of heel stick and pain was measured two times for each method before heel stick (baseline), and during heel stick (with intervention). The pain score was measured by the Premature Infant Pain Profile (PIPP). Results: The pain score during heel stick was significantly lowered with using facilitated tucking combined with non-nutritive sucking (4.87±2.583), facilitated tucking (6.68±2.344) and non-nutritive sucking (9.67±3.100) in comparison to the routine care method (11.57±3.510) of heel stick (P= .000). Combination of facilitated tucking with non- nutritive sucking was more effective than facilitated tucking or non-nutritive sucking (P= .000). Conclusion: Combination of facilitated tucking with non- nutritive sucking followed by facilitated tucking and non-nutritive sucking were effectively reduced pain scores more than routine care during heel-stick procedure. Combination of facilitated tucking with non- nutritive sucking is the most effective intervention that reduced PIPP scores among preterm infants during heel stick procedure. Recommendation: This study can be replicated on a large group of sample to validate the findings and to make generalizations and it can be taking up on other procedural pain that occur in neonatal intensive care units.