Osteosarcoma is a prevalent primary malignant bone tumor in young adults and adolescents, characterized by a high recurrence rate despite advancements in chemotherapy and surgical methods. This study investigated the effects of integrating high-dose methotrexate with cisplatin and paclitaxel on survival outcomes in osteosarcoma patients, and to identify prognostic factors influencing these outcomes. A retrospective analysis was conducted on 208 osteosarcoma patients treated between January 2013 and December 2018. Patients were divided into two groups: standard chemotherapy group (SC, n = 104) and cisplatin + paclitaxel + high-dose methotrexate (CPM, n = 104). The primary endpoints were progression-free survival (PFS) and overall survival (OS), while secondary endpoints included efficacy assessments. Kaplan-Meier survival curves were used to assess survival distributions, and statistical analyses were performed using SPSS 29.0. The CPM group demonstrated significantly longer PFS (16.85 +/- 3.40 months vs. 15.72 +/- 3.21 months, P = 0.015) and higher 5-year OS rates (54.81% vs. 40.38%, P = 0.037) compared to the SC group. Completion of chemotherapy and a response rate greater than 90% were identified as strong positive prognostic indicators. In contrast, pathologic fractures at diagnosis, lung metastases, and elevated lactate dehydrogenase levels were associated with poorer outcomes. Multivariate analysis underscored chemotherapy response and treatment adherence as independent survival predictors. The combination of cisplatin and paclitaxel with high-dose methotrexate significantly improves PFS and OS compared to standard chemotherapy. Moreover, treatment completion and achieving a chemotherapy response greater than 90% are critical factors for favorable prognosis.