Background Multimodal optical imaging, incorporating reflectance and fluorescence modalities, is a promising tool to detect oral premalignant lesions in real‐time. Methods Images were acquired from 171 sites in 66 patient visits for clinical evaluation of oral lesions. An automated algorithm was used to classify lesions as high‐ or low‐risk for neoplasia. Biopsies were acquired at clinically indicated sites and those classified as high‐risk by imaging, at the surgeon's discretion. Results Twenty sites were biopsied based on clinical examination or imaging. Of these, 12 were indicated clinically and by imaging; 58% were moderate dysplasia or worse. Four biopsies were indicated by imaging evaluation only; 75% were moderate dysplasia or worse. Finally, four biopsies were indicated by clinical evaluation only; 75% were moderate dysplasia or worse. Conclusion Multimodal imaging identified more cases of high‐grade dysplasia than clinical evaluation, and can improve detection of high grade precancer in patients with oral lesions.