Hypoxic microenvironment severely reduces therapeutic efficacy of oxygen-dependent photodynamic therapy in solid tumor due to the hampered cytotoxic oxygen radicals generation. Herein, a biocompatible nanoparticle (NP) is developed by combining bovine serum albumin, indocyanine green (ICG), and an oxygen-independent radicals generator (AIPH) for efficient sequential cancer therapy, denoted as BIA NPs. Upon near-infrared irradiation, the photothermal effect generated by ICG will induce rapid decomposition of AIPH to release cytotoxic alkyl radicals, leading to cancer cell death in both normoxic and hypoxic environments. Moreover, such nanosystem provides the highest AIPH loading capacity (14.9%) among all previously reported radical nanogenerators (generally from 5–8%). Additionally, the aggregation-quenched fluorescence of ICG molecules in the NPs can be gradually released and recovered upon irradiation enabling real-time drug release monitoring. More attractively, these BIA NPs exhibit remarkable anticancer effects both in vitro and in vivo, achieving 100% tumor elimination and 100% survival rate among 50 days treatment. These results highlight that this albumin-based nanoplatform is promising for high-performance cancer therapy circumventing hypoxic tumor environment and possessing great potential for future clinical translation.