Mutations in genes encoding histones, which package DNA into chromatin, have been identified as cancer drivers, yielding oncohistones. Most of the validated oncohistones support single amino acid mutations that occur at lysines that support histone posttranslational modification (PTM), which perturbs the histone PTM landscape. Here, we examine the oncogenicity of a series of globular domain histone H3 mutations in which any residue is mutated to a lysine, “H3 X to K,” which were identified as recurrent H3 missense mutations in human cancers. H3 X to K mutation promotes oncogenic growth in immortalized but untransformed human cells. Some H3 X to K mutations alter PTMs at proximal H3 residues. Bulk RNA sequencing comparing H3 X to K mutant expression with wildtype H3 expressing cells identifies alterations in expression of genes implicated in unique cancer-related pathways. To complement studies in human cells, we created a budding yeast model where we express H3 X to K mutants as the sole cellular copy of histone H3 or in the presence of wildtype H3, which simulates the dominant phenotype observed in human cancers. Expression of some H3 X to K mutations in yeast confer growth sensitivity to DNA damage and general cellular stress in a dominant fashion. Together, these studies suggest that H3 X to K mutation within the H3 globular domain creates bona-fide oncohistones that disrupt normal growth through altering histone PTMs, the transcriptome, and/or DNA damage repair.