Deep learning models often encounter challenges in making accurate inferences when there are domain shifts between the source and target data. This issue is particularly pronounced in clinical settings due to the scarcity of annotated data resulting from the professional and private nature of medical data. Despite the existence of decent solutions, many of them are hindered in clinical settings due to limitations in data collection and computational complexity. To tackle domain shifts in data-scarce medical scenarios, we propose a Random frequency filtering enabled Single-source Domain Generalization algorithm (RaffeSDG), which promises robust out-of-domain inference with segmentation models trained on a single-source domain. A filter-based data augmentation strategy is first proposed to promote domain variability within a single-source domain by introducing variations in frequency space and blending homologous samples. Then Gaussian filter-based structural saliency is also leveraged to learn robust representations across augmented samples, further facilitating the training of generalizable segmentation models. To validate the effectiveness of RaffeSDG, we conducted extensive experiments involving out-of-domain inference on segmentation tasks for three human tissues imaged by four diverse modalities. Through thorough investigations and comparisons, compelling evidence was observed in these experiments, demonstrating the potential and generalizability of RaffeSDG. The code is available at this https URL.