Skeletal fluorosis is a form of endemic disease caused by the excessive intake of fluoride. Bone deformation and periosteal calcification are the typical manifestations that can be observed in the images and are usually served as a basis of pathological grading. In the current medical systems, the diagnosis of skeletal fluorosis fully relies on doctors’ knowledge and experience, and no research effort has been made in automatic image information diagnostic systems. According to the image information, the shape of the lesion is irregular, the boundary is unclear and the lesion related pixels only occupy a small part of the image. We take the lead in proposing a two-stage scheme that can achieve automated X-ray image diagnosis and severity grading. In the first stage, a Dense U-Net is proposed for reliable lesion determination, and a multitype feature fusion approach passes effective and comprehensive features to the subsequent stage. In the second stage, a novel classifier is designed with the integration of ensemble learning and multiple instance learning, which can ensure classification accuracy in case that the feature for diagnosis only takes up a small proportion of the whole image. Through plenty of experiments on the actual data collected from the hospitals, it is verified that the proposed strategy can achieve satisfactory results on skeletal fluorosis image diagnosis and severity grading.