In search and rescue missions, drone operations are challenging and cognitively demanding. High levels of cognitive workload can affect rescuers’ performance, leading to failure with catastrophic outcomes. To face this problem, we propose a machine learning algorithm for real-time cognitive workload monitoring to understand if a search and rescue operator has to be replaced or if more resources are required. Our multimodal cognitive workload monitoring model combines the information of 25 features extracted from physiological signals, such as respiration, electrocardiogram, photoplethysmogram, and skin temperature, acquired in a noninvasive way. To reduce both subject and day inter-variability of the signals, we explore different feature normalization techniques, and introduce a novel weighted-learning method based on support vector machines suitable for subject-specific optimizations. On an unseen test set acquired from 34 volunteers, our proposed subject-specific model is able to distinguish between low and high cognitive workloads with an average accuracy of 87.3% and 91.2% while controlling a drone simulator using both a traditional controller and a new-generation controller, respectively.