The hypoxic microenvironment induced by sonodynamic therapy (SDT) via sonochemical oxygen consumption usually triggered tumor resistance to SDT, impeding therapeutic efficacy. In this sense, it was highly desired to tackle the hypoxia-related negative issues. Here we provide the therapeutic agents delivery system, TPZ/HMTNPs-SNO, which was constructed by loading tirapazamine (TPZ) into hollow mesoporous titanium dioxide nanoparticles (HMTNPs) with modification of S-nitrosothiol (R-SNO). Upon encountering ultrasound waves, the HMTNPs as sonosensitizers would generate reactive oxygen species (ROS) for SDT. In a sequential manner, the followed SDT-induced hypoxia further activated the “hypoxic cytotoxin”, TPZ, for hypoxia-specific killing effect. Meanwhile, the generated ROS could sensitize -SNO groups for on-demand nitric oxide (NO) release in an “anticancer therapeutic window”, resulting in the NO sensitized SDT effect. This study confirmed that the TPZ/HMTNPs-SNO with multi-mechanisms exploited the merits of synergistic combination of the three therapeutic modes, consequently potentiating the anticancer efficacy of SDT. Moreover, the echogenic property of NO made the nanoplatform as an ultrasound contrast agent to enhance ultrasound imaging. In this sense, we developed a sequential strategy for ultrasound mediated all-in-one nanotheranostic platform of TPZ/HMTNPs-SNO, which highlighted new possibilities of advancing cancer theranostics in biomedical fields.