The osteosarcoma tumor microenvironment has both cellular and non-cellular components. Among the cellular components, both immune and non-immune cells can be derived. The immune cells include infiltrating T lymphocytes, B cells, and dendritic cells, while the non-immune cells include macrophages and cancer-associated fibroblasts. The extracellular matrix, blood vessels, and all cytokines and chemokines are included in the non-cellular portion. Hypoxia-inducible factor-1α (HIF-1α) is up-regulated during the early stages of tumor formation due to an induced hypoxic drive. Tumor suppression, progression, or relapse may result from the interplay of various elements in the tumor microenvironment. Tumor suppression occurs when immune cells cooperate to eliminate cancer cells, whereas tumor formation occurs when an immunosuppressive microenvironment is created. Tumor growth or recurrence might result from some components of the tumor microenvironment releasing chemicals that hinder other immune cells from defending the tumor. T regulatory cells release the inhibitory cytokines interleukin (IL)-10 and IL-35, produce bioactive transforming growth factor beta (TGF-β), and induce death in effector T cells. Macrophages and dendritic cells produce HIF-1α, which directly reduces tumor cells’ vulnerability to doxorubicin (DOX)-induced apoptosis. Doxorubicin, narasin, ifosfamide, cisplatin, methotrexate, gemcitabine, etoposide, carboplatin, and cyclophosphamide have all been used to treat osteosarcoma. Modest doses of doxorubicin are recommended because of the cardiotoxic effects alone, but these leave some cancer cells alive. This review explicitly describes how the changes in the tumor microenvironment contribute specifically to doxorubicin resistance and how doxorubicin-resistant cells affect the components in the tumor microenvironment.