Combined autofluorescence (AF) and diffuse reflectance (DR) spectroscopies have been expected to offer enhanced diagnostic accuracies for noninvasive early detection of mucosa lesions, that is, oral cavity carcinoma and cervical carcinoma. This work reports on a hybrid AF and DR spectroscopic system that is developed for quantification and diagnosis of mucosa abnormalities. The system stability and reliability are firstly assessed by phantom experiments, showing a measurement variation lower than 1% within 20 min. In vitro and in vivo validations are then conducted for tissue identification and lesion differentiation. For enhanced decision, a data‐driven diagnosis algorithm is explored in pilot under different experimental configurations. The results conclude a promising accuracy of >96% for the in vivo classification as well as an excellent sensitivity of >88% for the in vitro mucosa lesions detection, and demonstrate sound potential of the system in early detection of mucosa lesions.