Hypoxia is a common feature of malignant tumors, which can accelerate tumor growth and reduce the sensitivity of chemotherapy and sonodynamic therapy by activating the hypoxia-inducible factor (HIF) signaling pathway. In HER2-positive gastric cancer, HER2 overexpression enhances HIF-1α synthesis, exacerbating hypoxia and impairing sonodynamic therapy. It also reduces trastuzumab-mediated antibody-dependent cytotoxicity, significantly compromising therapeutic outcomes. Herein, pyropheophorbide-conjugated lipid (pyropheophorbide-lipid, PL) and trastuzumab were fabricated into targeted nanoparticles (TP NPs) for loading perfluorobromooctane (PFOB) carrying oxygen (TPPO NPs), thus enabling oxygen self-supplied sonodynamic and antibody therapies. In vitro experiments showed that antibody targeting significantly increased the cellular uptake of sonosensitizers, and the controlled release of oxygen was dependent on ultrasound parameters, greatly enhancing the killing effects of SDT and antibody therapy. In vivo animal experiments showed that TPPO NPs-mediated enhanced permeation and retention (EPR) effects, along with antibody targeting, improved the enrichment of sonosensitizers in tumors. Notably, ultrasound-triggered topical delivery of oxygen significantly alleviated tumor hypoxia and further improved the efficacy of SDT and antibody therapy. Given the good biosafety profile of TPPO NPs, this system holds great promise for future clinical applications in gastric cancer.