Background: Insufficient drug targeting and the immunosuppressive tumor microenvironment are key factors contributing to the high mortality rate of hepatocellular carcinoma (HCC). The targeted cavitation effect mediated by low-intensity pulsed ultrasound (LIPUS) provides a promising strategy to address these challenges. Although Piezo1 is known to be dysregulated in multiple cancer types, it remains unclear whether ultrasound stimulation can activate Piezo1 and trigger downstream cell death and immune activation. Methods: Perfluoropentane (PFP)@R-Lip was prepared to assess its combined effects with LIPUS on proliferation, migration, invasion, apoptosis, and ferroptosis in HCC cells. The specific Piezo1 inhibitor GsMTx4 was used to verify the role of Piezo1 activation and immunogenic cell death (ICD) induction. A tumor-bearing mouse model was established to validate the in vivo antitumor efficacy of LIPUS combined with PFP@R-Lip. Student’s t-test, one-way ANOVA test, and two-way ANOVA test were used. Results: PFP@R-Lip was successfully prepared and exhibited enhanced targeting ability to HCC cells. The combination of LIPUS and PFP@R-Lip inhibited the proliferation, migration, invasion, and cell cycle of HCC cells. Mechanistically, the combination activated the Piezo1 channel, leading to intracellular calcium overload, mitochondrial membrane potential (MMP) depolarization, and reactive oxygen species (ROS) accumulation. This cascade induced both apoptosis and ferroptosis, ultimately triggering ICD. These effects were partially reversed by pretreatment with GsMTx4. Conclusions: PFP@R-Lip with ultrasound imaging properties and tumor-targeting specificity was developed. LIPUS combined with PFP@R-Lip was verified to induce intracellular calcium overload and synergistically trigger apoptosis and ferroptosis to prompt ICD in HCC via Piezo1 activation.