Ultrasound offers a noninvasive, clinically relevant means to achieve precise spatiotemporal control of cargo release from ultrasound-responsive drug delivery systems within deep tissues. This approach enables targeted delivery of therapeutic agents, enhancing efficacy while minimizing systemic toxicity. While previous studies show that release from ultrasound-responsive liposomes depends on acoustic parameters, the underlying mechanisms remain unclear. A deeper mechanistic understanding is essential to achieve precision over release and maximize therapeutic outcomes. To address this, we propose a sonoporation-based framework to describe release dynamics across varying frequencies, pressures, duty cycles, and pulse repetition frequencies for ultrasound-responsive poly(ethylene glycol)-functionalized liposomes. Using computational simulations validated by empirical results, our framework identifies a critical pressure threshold for release onset and demonstrates how the time spent above this threshold, modulated by acoustic parameters, governs release efficiency. To elucidate these effects, custom-built ultrasound transducers with different resonance frequencies were fabricated and characterized to ensure precise sample alignment, minimize acoustic distortion, and maintain a controlled focal-volume-to-sample-volume ratio across different frequencies. COMSOL simulations indicated that oscillatory acoustic pressure plays a more dominant role than acoustic radiation force, while coarse-grained molecular dynamics simulations captured pressure-dependent pore formation dynamics within the lipid bilayer. Together, our experiments and simulations highlight mechanical effects—particularly oscillatory acoustic pressure—as the primary driver of sonoporation-facilitated release. Finally, we discuss how optimizing acoustic parameters through this mechanistic framework could facilitate safe and effective clinical translation by considering tissue safety and ultrasound transducer design.