The acetylation of histones H2A on lysine 5 (H2AacK5) and H3 on lysine 27 (H3AcK27) modulate several cellular mechanisms through the p300 enzyme in pathological lesions; however, their role in odontogenic lesions has not been addressed. This study aims to evaluate the immunoexpression of p300, H2AacK5, and H3AcK27 in samples of ameloblastoma (AMB) (n = 30), odontogenic keratocyst (OK) (n = 15), adenomatoid odontogenic tumor (AOT) (n = 10), odontogenic fibroma (OF) (n = 8), calcifying odontogenic cyst (COC) (n = 8), odontogenic myxoma (MIX) (n = 10), and ameloblastic fibroma (AF) (n = 06). The percentage of p300-positive cells was higher in AOT and decreased in COC, OK, AMB, AF, OF, and MIX. H2AacK5-positive cells were higher in AF and decreased in AOT, COC, OK, OF, AMB, and MIX, whereas H3acK27-positive cells were higher in AOT and decreased in COC, OK, AF, OF, AMB, and MIX. The expression of these proteins was higher in nonaggressive lesions in comparison to aggressive lesions. There was a positive correlation between p300 and H2AacK5, and H3acK27 in AMB, MIX, and OF, whereas there was a positive correlation between p300 and H2AacK5 in AOT and COC. The histone acetylation may be involved in the biological behavior of these lesions, which could be used to improve their diagnosis and treatment.