Human serum albumin (HSA) is a versatile, biodegradable, biocompatible, non-toxic, and non-immunogenic protein nanocarrier, making it an ideal platform for developing advanced drug delivery systems. These properties have garnered significant attention in utilizing HSA nanoparticles for the safe and efficient delivery of chemotherapeutic agents. HSA-based nanoparticles can be surface-modified with various ligands to enable tumor-targeted drug delivery, enhancing therapeutic specificity and efficacy. Furthermore, the multifunctionality of HSA nanoparticles offers promising strategies to overcome challenges in cancer therapy, including poor bioavailability, off-target toxicity, and drug resistance. This review highlights the structural features of HSA, explores its diverse modifications to improve drug-binding affinity and targeting ability, and discusses its potential as a multifunctional carrier in oncology. By summarizing the latest advances in HSA modification techniques and applications, this review provides a comprehensive perspective on the future of protein-based drug delivery systems in tumor therapy.