•Autofluorescence and chemiluminescence are used in the diagnosis of oral cavity lesions.•Both test have a high sensitivity in the diagnosis of dysplastic and malignant lesions.•Both tests have a low specificity in the diagnosis of dysplastic and malignant lesions.•Both tests may have a role in the context of oral cancer screening programs.•Further studies should be encouraged to clarify the cost-benefit ratio. To define the accuracy of autofluorescence-based (AF) and chemiluminescence-based (CL) systems in the diagnosis of oral dysplastic and malignant lesions in addition to the Conventional Oral Examination (COE). The study was performed according to the PRISMA-DTA guidelines. A total of 2631 oral cavity lesions (AF, n = 2076; CL, n = 555) from 26 studies (AF = 17; CL = 9) was used for calculation of diagnostic accuracy parameters. The overall pooled sensitivity and specificity of the AF were 81.3% (95% CI: 74.3% − 87.5%) and 52.1% (95% CI: 36.9% − 67.1%), respectively. Cumulative diagnostic odds ratio (DOR) was 5.44 (95% CI: 2.29 – 10.56) with a significant heterogeneity between studies (I2 = 80.7%, 95% CI: 70.0% − 86.7%; p < .05). The overall pooled sensitivity and specificity for the CL were 84.9% (95% CI: 66.7% − 96.7%) and 51.8% (95% CI: 37.3% − 65.9%), respectively. The overall pooled DOR was 8.59 (95% CI: 2.11 – 22.38) with a significant heterogeneity between studies (I2 = 65.4%, 95% CI: 29.6% − 83.0%; p < .05). AF and CL present a high sensitivity in the diagnosis of dysplastic and malignant oral cavity lesions, demonstrating that diagnostic biopsies may be avoided in case of a negative test result. Both tests have a low specificity, and the reduction of the false positive rate compared to the COE alone remains poor.