A novel multifunctional nanotheranostic agent with targeting, redox‐responsive ultrasound imaging and ultrasound imaging‐guided high‐intensity focused ultrasound (HIFU) therapy (MSNC‐PEG‐HASS‐PFH, abbreviated as MPHSS‐PFH) capabilities is developed. The redox‐responsive guest molecule release and ultrasound imaging functions can be both integrated in such a “smart” theranostic agent, which is accomplished by the redox‐triggered transition from the crosslinking state to retrocrosslinking state of the grafted polyethylene glycol‐disulfide hyaluronic acid molecules on the particle surface when reaching a reducing environment in vitro. More importantly, under the tailored ultrasound imaging guiding, in vivo Hela tumor‐bearing nude mice can be thoroughly and spatial‐accurately ablated during HIFU therapy, due to the targeted accumulation, responsive ultrasound imaging guidance and the synergistic ablation functions of nanotheranostic agent MPHSS‐PFH in the tumors. This novel multifunctional nano‐platform can serve as a promising candidate for further studies on oncology therapy, due to its high stability, responsive and indicative ultrasound imaging of tumors, and enhanced HIFU therapeutic efficiency and spatial accuracy under ultrasound‐guidance. Can a nanosized agent efficiently respond to ultrasound? A multifunctional redox‐responsive complex decorated, ultrasound sensitive PFH encapsulated nanotheranostic agent has been successfully constructed, which can be activated by the internal reducing environment and the external HIFU stimulus to enable tailored ultrasound guided synergistic HIFU therapy duo to its redox‐responsive ultrasound imaging and PFH bubble cavitations/thermal effects.