Osteosarcoma, a prevalent primary malignant bone tumor, predominantly affects both elderly and adolescent populations and usually has an unfavorable prognosis. The specific mechanisms underlying its invasive progression remain unclear. The tumor microenvironment includes not only cancer cells but also bone-related cells, immune cells, tumor-associated nerve cells, and cell-secreted factors. The cooperative and competitive interactions among these cellular components contribute to the proliferation, progression, metastasis, and immune evasion of osteosarcoma. Alterations in bone-related cells, resulting from oncogenic changes, can rapidly increase bone density or aggravate bone loss, thereby promoting the survival of osteosarcoma cells. During the progression of osteosarcoma, genetic alterations in tumor cells lead to changes in extracellular matrix components, influencing the variation in cell-secreted factors, promoting immunosuppression within the tumor microenvironment, and consequently affecting tumor proliferation and progression. This review summarizes the roles of tumor microenvironment components in the pathogenesis of osteosarcoma and discusses existing therapeutic targets. The findings suggest potential research directions for further investigation of osteosarcoma, provide novel insights into the development of osteosarcoma, and may guide the development of more effective anti-tumor strategies.