Background.A variety of natural and synthetic agents have recently been used in clinical trials to arrest dentin caries.Objectives. The aim of the present study was to explore the remineralization and antibacterial effect of natural (propolis, hesperidin) vs. synthetic (silver diamine fluoride (SDF)) agents on deep carious dentin. Material and methods.A total of 64 human molar teeth with Class I caries were randomly distributed into 4 groups: control group; propolis group; hesperidin group; and SDF group. The cavities were prepared using the stepwise caries removal technique, and then covered with the materials to be tested. The samples were taken from the carious lesions before and after treatment to evaluate the antibacterial effect. Then, the teeth were restored with a glass ionomer cement (GIC). Digital X-rays were taken to assess remineralization and the antibacterial effect after 6 and 12 weeks.Results. The highest value of radiodensity was observed in the propolis group (46.44 ±9.65 HU), while the lowest value was noted in the hesperidin group (12.62 ±5.86 HU). The bacterial count in the propolis group was 1,280.00 ±1,480.54 CFU/mL at baseline, which was not significantly higher than the value measured after 6 weeks (574.00 ±642.48 CFU/mL; p = 0.153), whereas in the hesperidin group, the mean value of the bacterial count at baseline (3,166.67 ±1,940.79) was not much higher as compared to the value obtained at 6 weeks (2,983.33 ±1,705.77) (p = 0.150). Conclusions.In comparison with SDF, propolis and hesperidin agents showed promising effects in terms of remineralization of carious dental tissue and hindering the progression of caries.