Real-time acousto-optic (AO) sensing has been shown to noninvasively detect changes in ex vivo tissue optical properties during high-intensity focused ultrasound (HIFU) exposures. The technique is particularly appropriate for monitoring noncavitating lesions that offer minimal acoustic contrast. A numerical model is presented for an AO-guided HIFU system with an illumination wavelength of 1064 nm and an acoustic frequency of 1.1 MHz. To confirm the model’s accuracy, it is compared to previously published experimental data gathered during AO-guided HIFU in chicken breast. The model is used to determine an optimal design for an AO-guided HIFU system, to assess its robustness, and to predict its efficacy for the ablation of large volumes. It was found that a through transmission geometry results in the best performance, and an optical wavelength around 800 nm was optimal as it provided sufficient contrast with low absorption. Finally, it was shown that the strategy employed while treating large volumes with AO guidance has a major impact on the resulting necrotic volume and symmetry.