Healthcare systems have recently utilized the Internet of Medical Things (IoMT) to assist intelligent data collection and decision-making. However, the volume of malicious threats, particularly new variants of malware attacks to the connected medical devices and their connected system, has risen significantly in recent years, which poses a critical threat to patients’ confidential data and the safety of the healthcare systems. To address the high complexity of conventional software-based detection techniques, Hardware-supported Malware Detection (HMD) has proved to be efficient for detecting malware at the processors’ micro-architecture level with the aid of Machine Learning (ML) techniques applied to Hardware Performance Counter (HPC) data. In this work, we examine the suitability of various standard ML classifiers for zero-day malware detection on new data streams in the real-world operation of IoMT devices and demonstrate that such methods are not capable of detecting unknown malware signatures with a high detection rate. In response, we propose a hybrid and adaptive image-based framework based on Deep Learning and Deep Reinforcement Learning (DRL) for online hardware-assisted zero-day malware detection in IoMT devices. Our proposed method dynamically selects the best DNN-based malware detector at run-time customized for each device from a pool of highly efficient models continuously trained on all stream data. It first converts tabular hardware-based data (HPC events) into small-size images and then leverages a transfer learning technique to retrain and enhance the Deep Neural Network (DNN) based model’s performance for unknown malware detection. Multiple DNN models are trained on various stream data continuously to form an inclusive model pool. Next, a DRL-based agent constructed with two Multi-Layer Perceptrons (MLPs) is trained (one acts as an Actor and another acts as a Critic) to align the decision of selecting the most optimal DNN model for highly accurate zero-day malware detection at run-time using a limited number of hardware events. The experimental results demonstrate that our proposed AI-enabled method achieves 99\% detection rate in both F1-score and AUC, with only 0.01\% false positive rate and 1\% false negative rate.