Non-invasive multi-disease detection is an active technology that detects human diseases automatically. By observing images of the human body, computers can make inferences on disease detection based on artificial intelligence and computer vision techniques. The sublingual vein, lying on the lower part of the human tongue, is a critical identifier in non-invasive multi-disease detection, reflecting health status. However, few studies have fully investigated non-invasive multi-disease detection via the sublingual vein using a quantitative method. In this paper, a two-phase sublingual-based disease detection framework for non-invasive multi-disease detection was proposed. In this framework, sublingual vein region segmentation was performed on each image in the first phase to achieve the region with the highest probability of covering the sublingual vein. In the second phase, features in this region were extracted, and multi-class classification was applied to these features to output a detection result. To better represent the characterisation of the obtained sublingual vein region, multi-feature representations were generated of the sublingual vein region (based on color, texture, shape, and latent representation). The effectiveness of sublingual-based multi-disease detection was quantitatively evaluated, and the proposed framework was based on 1103 sublingual vein images from patients in different health status categories. The best multi-feature representation was generated based on color, texture, and latent representation features with the highest accuracy of 98.05%.