Cardiopulmonary resuscitation (CPR) is a crucial medical technique that is performed manually to preserve intact brain function. Early initiation of CPR manoeuvres and activation of the chain of survival are key factors in the prognosis of patients with cardiorespiratory arrest (CRA). Inadequacy in any step of CPR due to a lack of knowledge or skill is associated with a poor return of spontaneous circulation and a decreased survival rate. To assess the knowledge, attitude, practice, and factors associated with health towards CPR at Ayder Comprehensive Specialized Hospital 2023. Institution-based cross-sectional study was conducted to assess the knowledge, attitude, and practice of health professionals towards cardiopulmonary CPR in Ayder Comprehensive Specialized Hospital Of Tigray, Ethiopia from 1 May to 30 August 2023. Data were collected using structured questionnaires by Two BSC anaesthesia staff and One MSc. as supervisor. A stratified random sampling technique was used to select the study participants. The Data were entered and analyzed using SPSS version 23. Variables with P value less than 0.20 were fitted into multivariate logistic regression. Descriptive statistics such as frequencies, median, interquartile range, percentages, tables, graphs and charts were used to present the results. A total of 262 Of 277 healthcare providers were included in the study, with a response rate of 93.3%. Knowledge, attitude, practice of health professionals towards CPR was 22.5%, 39% and 31.5%, respectively. MSc degree in level of education [adjusted odds ratio (AOR): 8.561 95% CI=2.109-34.746], CPR training (AOR: 2.157, 95%, 1.005, 4.631), and Work experience 6-10years and more than 10 (AOR =0.195, 95% CI, 0.071-0.539) and AOR =0.148 195 95% CI, 0.017, 1.285) were significantly associated with knowledge. The Anaesthetist and Medical doctors were 5.5 times (AOR, 5.50, 95% CI 1.263-23.93) and 2.125 times (AOR: 2.125, 95% CI, 0.865-5.216) respectively more likely to have favourable attitude than the midwives. Regarding to practice participants with CPR training (AOR: 1.804 95% CI=0.925-3.518), good knowledge (AOR: 2.766 95% CI=1.312-5.836) and favourable attitude (AOR: 1.931, 95% CI=0.995-3.749) were significantly associated with safe practice. The overall level of health professionals, knowledge, attitude, practices, and factors associated towards CPR in Ayder Comprehensive Specialized Hospital at Tigray, Ethiopia were insufficient, favourable and safe enough. Regular CPR training is recommended to increase the knowledge, attitude, and practice of healthcare professionals towards CPR.