De novo DNA methylation by DNMT3A is a fundamental epigenetic modification for transcriptional regulation during cellular development and differentiation. The establishment of appropriate DNA methylation patterns in the human genome involves a crosstalk between DNMT3A, histone tails, regulatory proteins and RNAs. Mutations in DNMT3A and disruptions to this crosstalk of DNMT3A have been reported in several diseases, including Acute Myeloid Leukemia (AML). We sought to model how previously uncharacterized mutations in DNMT3A contribute to the aberrant DNA methylation observed in AML. We then sought to better understand the relative roles of histone tails, regulatory proteins and RNAs in the simultaneous modulation of DNMT3A activity and identified two molecules that inhibit protein interactions with DNTM3A. Although 22% of all AML patients exhibit mutations throughout the DNMT3A gene, the effect of many mutations on DNMT3A activity remain uncharacterized. Moreover, little is known of the interactions between DNMT3A mutants and regulatory proteins, or conversely, mutant regulatory proteins and wild type DNMT3A. We show that previously unexplored DNMT3A mutations dramatically alter the enzyme’s ability to perform CpG and non-CpG methylation as well as the ability of partner proteins to modulate enzymatic activity. Additionally, cell-based studies of one of these DNMT3A mutations (S714C) replicated our findings in vitro showing a dramatic loss of genome-wide methylation. We found that p53 decreases DNMT3A activity by forming a heterotetramer complex with DNMT3A, and while p53 binds DNMT3A R882H, repression of DNMT3A activity is blocked by this substitution. Using p53 as an example, we also show that cancer-related substitutions to p53 are unable to disrupt DNMT3A heterotetramers, unlike that observed for WT p53. To provide insights into the crosstalk between DNMT3A and distinct epigenetic mechanisms we initially assessed the relative of role of regulatory proteins and histone tails in the simultaneous modulation of DNMT3A activity. Using radiochemical and binding assays under distinct conditions and with biologically relevant substrates, we found that regulatory proteins play dominant roles in the modulation of DNMT3A activity. Furthermore, we provide evidence that the activity of DNMT3A is not limited to DNA that is part of the initial DNMT3A–nucleosome complex. We then expanded on these findings by carrying out similar studies that included non-coding RNAs. We show regulatory RNAs play a dominant role over additional epigenetic mechanisms in the simultaneous modulation of DNMT3A. Additionally, we present evidence that is inconsistent with a model for RNA regulation of DNMT3A that relies on the formation of localized RNA/DNA structures. Lastly, a screen of a diverse small molecule library identified two compounds that act as inhibitors of protein-protein interactions (PPIs) with DNMT3A. Thus, presenting a basis for manipulating the allosteric regulation of DNMT3A.