Osteosarcoma, the most prevalent primary bone malignancy in children and adolescents, poses significant challenges due to its aggressive nature and propensity for metastasis. Despite advances in treatment, survival rates for high‑risk patients remain unsatisfactory, underscoring the urgent need for innovative approaches. This review explores the vital role of multi‑omics‑integrating genomics, transcriptomics, proteomics and metabolomics‑in unraveling the complex biological landscapes of osteosarcoma. By providing comprehensive insights into tumor heterogeneity, signaling pathways and metabolic reprogramming, multi‑omics facilitates the identification of novel biomarkers and therapeutic targets. The objective of the present study was to highlight the transformative potential of multi‑omics in enhancing the understanding and management of osteosarcoma, ultimately paving the way for personalized treatment strategies and improved patient outcomes. Through this synthesis, the study calls for a concerted effort to integrate multi‑omics into clinical practice, fostering a more precise approach to osteosarcoma care.