Background Conventional risk score for predicting in-hospital mortality following Acute Coronary Syndrome (ACS) is not catered for Asian patients and requires different types of scoring algorithms for STEMI and NSTEMI patients. Objective To derive a single algorithm using deep learning and machine learning for the prediction and identification of factors associated with in-hospital mortality in Asian patients with ACS and to compare performance to a conventional risk score. Methods The Malaysian National Cardiovascular Disease Database (NCVD) registry, is a multi-ethnic, heterogeneous database spanning from 2006–2017. It was used for in-hospital mortality model development with 54 variables considered for patients with STEMI and Non-STEMI (NSTEMI). Mortality prediction was analyzed using feature selection methods with machine learning algorithms. Deep learning algorithm using features selected from machine learning was compared to Thrombolysis in Myocardial Infarction (TIMI) score. Results A total of 68528 patients were included in the analysis. Deep learning models constructed using all features and selected features from machine learning resulted in higher performance than machine learning and TIMI risk score (p < 0.0001 for all). The best model in this study is the combination of features selected from the SVM algorithm with a deep learning classifier. The DL (SVM selected var) algorithm demonstrated the highest predictive performance with the least number of predictors (14 predictors) for in-hospital prediction of STEMI patients (AUC = 0.96, 95% CI: 0.95–0.96). In NSTEMI in-hospital prediction, DL (RF selected var) (AUC = 0.96, 95% CI: 0.95–0.96, reported slightly higher AUC compared to DL (SVM selected var) (AUC = 0.95, 95% CI: 0.94–0.95). There was no significant difference between DL (SVM selected var) algorithm and DL (RF selected var) algorithm (p = 0.5). When compared to the DL (SVM selected var) model, the TIMI score underestimates patients’ risk of mortality. TIMI risk score correctly identified 13.08% of the high-risk patient’s non-survival vs 24.7% for the DL model and 4.65% vs 19.7% of the high-risk patient’s non-survival for NSTEMI. Age, heart rate, Killip class, cardiac catheterization, oral hypoglycemia use and antiarrhythmic agent were found to be common predictors of in-hospital mortality across all ML feature selection models in this study. The final algorithm was converted into an online tool with a database for continuous data archiving for prospective validation. Conclusions ACS patients were better classified using a combination of machine learning and deep learning in a multi-ethnic Asian population when compared to TIMI scoring. Machine learning enables the identification of distinct factors in individual Asian populations to improve mortality prediction. Continuous testing and validation will allow for better risk stratification in the future, potentially altering management and outcomes.