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Aim: The aim of this study was to investigate the possible therapeutic impacts of two pineal hormones, melatonin and 5-methoxytryptophol (5-MTX), in a rat model of acute pulpitis by analyzing biochemical and histopathological parameters., Methods: This research was done using 32 male and female Wistar albino rats with weight between 200 and 250 g. The rats were randomly divided into four groups: a control group (rats without any treatment), acute pulpitis (AP) group, AP+melatonin group, and AP+5-MTX group. In the AP-induced groups, the crowns of the upper left incisors were removed horizontally. Lipopolysaccharide solution was applied to the exposed pulp tissue before the canal orifices were sealed with a temporary filling material. Melatonin (10 mg/kg) and 5-MTX (5 mg/kg) were administered intraperitoneally. The rats were sacrificed 24 hours after pulp injury, and trunk blood and pulp samples were collected. The concentrations of TNF- α , IL-1 β , MMP-1, and MMP-2 in sera and pulp samples were determined using ELISA assay kits., Results: TNF- α , IL-1 β , MMP-1, and MMP-2 levels in the serum and pulp tissues were considerably higher in the AP group than the control group ( p < 0.01-0.001). In the AP+melatonin and AP+5-MTX groups, TNF- α , IL-1 β , MMP-1, and MMP-2 levels in the serum and pulp tissues were significantly lower than in the AP group ( p < 0.05-0.001)., Conclusions: Both melatonin and 5-MTX provided protective effects on acute pulpitis, which indicates they may be promising as a therapeutic strategy for oral disease., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Fatma Kermeoğlu et al.)