This study evaluated the synergistic effect of proanthocyanidin (PA) and casein phosphopeptide amorphous calcium fluoride phosphate (CPP-ACFP) on remineralization of artificial root caries. Demineralized root fragments (n = 90) were randomly divided into six groups based on treatments: (1) 6.5% PA; (2) CPP-ACP; (3) CPP-ACFP; (4) CPP-ACFP + 6.5% PA; (5) 1000 ppm fluoride; and (6) deionized water (control). Each specimen was immersed in demineralizing solution for 14 h, testing solutions/pastes for 2 h, remineralizing solution for 8 h and pH cycling was performed at 37°C for 8 days. Specimens were evaluated using transverse microradiography (lesion depth and mineral loss), Knoop microhardness and confocal laser scanning microscopy. Lesion depth was significantly lower in CPP-ACFP+PA and 1000 ppm fluoride groups (p < 0.001) with no significant difference between the two groups (p > 0.05). Mineral loss was the lowest in CPP-ACFP+PA group (p < 0.05). Fluoride and CPP-ACFP groups showed similar mineral gain (p > 0.05). Artificial caries lesions treated with CPP-ACFP+PA showed significantly higher microhardness values at 130 μm and 150 μm from the surface (p < 0.05). Combined use of PA and CPP-ACFP has a synergistic effect on root caries remineralization by enhancing mineral gain and increasing hardness of artificial root caries.