<p>Lymphoma can seriously affect the quality of life of patients. Both homoharringtonine (HHT) and tanshinone IIA (Tan IIA) have shown robust anti-proliferation and apoptosis-inducing effects in lymphoma cells. However, it is unclear whether they can be used in combination to treat acute myeloid leukemia and lymphoma. Cell Counting Kit-8 (CCK-8) was employed to measure cell viability, the 5-Ethynyl-20-deoxyuridine assay (EdU) was used to quantify cell proliferation, and the transwell migration assay was used to assess cell migration in U937 and Raji cells. Additionally, transmission electron microscopy and nanoparticle tracking analysis assays were used to observe and identify exosomal structure, respectively. Combined HHT and Tan IIA treatment synergistically inhibited the viability and proliferation of U937 and Raji cells, induced apoptosis, and reduced vascular endothelial growth factor (VEGF) levels in these cells. Additionally, VEGFA and VEGFC levels were significantly reduced in exosomes derived from Raji cells that had been treated with HHT and Tan IIA (Exo^{HHT + Tan IIA}). Moreover, absorption of Exo^{HHT + Tan IIA} significantly inhibited the viability, proliferation, and migration of human umbilical vein endothelial cells by downregulating the expression of serine/threonine kinase 1 (Akt), matrix metalloproteinase-2 (MMP2) and MMP9. Exo^{HHT + Tan IIA} suppressed the tumor microenvironment. HHT and Tan IIA combined therapy synergistically suppressed lymphoma progression by downregulating the Akt/MMP signaling pathway, suggesting their use in treating lymphomas.</p><p>Clinical trial number: Not applicable.</p>