Entamoeba histolytica (E. histolytica) is an anaerobic parasite that causes Amoebiasis in the intestine or extraintestinal, with immunology, genetics, and environmental variables all playing a part in the disease's development, but its molecular mechanism is unknown. One of the primary obstacles in understanding the etiology of Amoebiasis will be identifying the genetics profiling that controls the amoebiasis network. By examining the gene expression profile of Amoebiasis and comparing it to healthy controls, we were able to identify differentially expressed genes (DEGs). Differentially expressed genes were used to build the amoebiasis protein interaction network and calculated its network topological properties. We discovered that nine key hub genes(KHGs) are JUN, PTGS2, FCGR3A, MNDA, CYBB, EGR1, CCL2, TLR8, and LRRK2 genes. The genes JUN and EGR1 were transcriptional factors (TFs) and up-regulated, others down-regulated. hsa-miR-155-5p,hsa-miR-101-3p,hsa-miR-124-3p,hsa-miR-26b-5p and hsa-miR-16-5p are also among the essential miRNAs that have been demonstrated to be targeted by key hub genes. These KHGs were primarily enriched in the IL-17 signaling pathway, TNF signaling pathway, NOD-like receptor signaling pathway, Toll-like receptor signaling pathway. miRNAs were grouped in various pathways, focusing on the TGF−beta signaling pathway, Human immunodeficiency virus 1 infection, Insulin signaling pathway, Signaling pathways regulating pluripotency of stem cells, etc. Amoebiasis KHGs (JUN, PTGS2, CCL2, MNDA) and their associated miRNAs are the primary targets for therapeutic methods and possible biomarkers. Furthermore, we identified drugs for genes JUN, PTGS2, FCGR3A, CCL2, and LRRK2. KHGs, on the other hand, required experimental validation to prove their efficacy.