Histone methyltransferases (HMTs) comprise a subclass of epigenetic regulators. Dysregulation of these enzymes results in aberrant epigenetic regulation, commonly observed in various tumor types, including hepatocellular adenocarcinoma (HCC). Probably, these epigenetic changes could lead to tumorigenesis processes. To predict how histone methyltransferase genes and their genetic alterations (somatic mutations, somatic copy number alterations, and gene expression changes) are involved in hepatocellular adenocarcinoma processes, we performed an integrated computational analysis of genetic alterations in 50 HMT genes present in hepatocellular adenocarcinoma. Biological data were obtained through the public repository with 360 samples from patients with hepatocellular carcinoma. Through these biological data, we identified 10 HMT genes ( SETDB1, ASH1L, SMYD2, SMYD3, EHMT2, SETD3, PRDM14, PRDM16, KMT2C, and NSD3) with a significant genetic alteration rate (14%) within 360 samples. Of these 10 HMT genes, KMT2C and ASH1L have the highest mutation rate in HCC samples, 5.6% and 2.8%, respectively. Regarding somatic copy number alteration, ASH1L and SETDB1 are amplified in several samples, while SETD3, PRDM14, and NSD3 showed a high rate of large deletion. Finally, SETDB1, SETD3, PRDM14, and NSD3 could play an important role in the progression of hepatocellular adenocarcinoma since alterations in these genes lead to a decrease in patient survival, unlike patients who present these genes without genetic alterations. Our computational analysis provides new insights that help to understand how HMTs are associated with hepatocellular carcinoma, as well as provide a basis for future experimental investigations using HMTs as genetic targets against hepatocellular carcinoma.