Optical coherence tomography (OCT) is a potential clinical tool for enamel lesion monitoring. Swept-source OCT findings were compared with cross-sectional nanohardness findings of enamel. Subsurface bovine enamel lesions in three groups were subjected to (1) deionized water (control), (2) phosphoryl oligosaccharide of calcium (POs-Ca) or (3) POs-Ca with 1 ppm fluoride for 14 days. B-scans images were obtained at 1310-nm center wavelength on sound, demineralized and remineralized areas after 4, 7, and 14 days. The specimens were processed for cross-sectional nanoindentation. Reflectivity from enamel that had increased with demineralization decreased with remineralization. An OCT attenuation coefficient parameter ($μt$), derived based on the Beer-Lambert law as a function of backscatter signal slope, showed a strong linear regression with integrated nanohardness of all regions ($p<0.001$, $r=−0.97$). Sound enamel showed the smallest, while demineralized enamel showed the highest $μt$. In group three, $μt$ was significantly lower at four days than baseline, but remained constant afterwards. In group two, the changes were rather gradual. There was no significant difference between groups two and three at 14 days in nanohardness or $μt$ POs-Ca with fluoride-enhanced nanohardness of the superficial zone. OCT signal attenuation demonstrated a capability for monitoring changes of enamel lesions during remineralization.