Background: Hypoxic ischemic encephalopathy is one of the most serious and life-threatening types of infant brain damage that can occur during childbirth that affects all aspects of infant's life. This complex disorder requires caregivers that have sufficient knowledge of the basics of hypoxic ischemic encephalopathy and be more aware of the relevant care strategies provided the disease. Aim: This study aims to assess caregivers' awareness about neonate hypoxic ischemic encephalopathy and subsequent infant development. Research design: A descriptive design. Subject: A convenient sample of 45 caregivers and a purposive sample of their hospitalized neonates. Setting: The neonatal intensive care units at Maternity and Gynecological Hospital and Children's Hospitals affiliated to Ain Shams University, Egypt. Methods: three tools were used to conduct the study. Tool 1) Pre-designed questionnaire sheet. Tool 2) Caregivers self- reported practices format. Tool 3) Caregiver's spiritual and psychological well-being Scales toward children with hypoxic ischemic encephalopathy. Results: nearly three quarters of studied caregivers had unsatisfactory knowledge, most of the studied caregivers had incompetent practice, two fifths of them had low spiritual well-being, and two thirds of the studied caregivers have poor psychological well-being. Conclusion: There was also highly statistically significant relation between total knowledge of caregivers and their education level and residence. In addition, there was a highly statistically significant relation between total self-reported and their age and education level. There was highly statistically significant positive correlation between all domains listed. Recommendations: Continuous health education programs are necessary to improve caregivers ' adjustments toward the care of their hypoxic ischemic encephalopathy infant through discussing infant needs and reassuring the importance of follow-up care.