Radiation therapy (RT) has traditionally not been widely used in the management of hepatic malignancies for fear of toxicity in the form of radiation-induced liver disease (RILD). Pre-clinical hepatic irradiation models can provide clinicians with better understanding of the radiation tolerance of the liver, which in turn may lead to the development of more effective cancer treatments. Previous models of hepatic irradiation are limited by either invasive laparotomy procedures, or the need to irradiate the whole or large parts of the liver using external skin markers. In the setting of modern-day radiation oncology, a truly translational animal model would require the ability to deliver RT to specific parts of the liver, through non-invasive image guidance methods. To this end, we developed a targeted hepatic irradiation model on the Small Animal Radiation Research Platform (SARRP) using contrast-enhanced cone-beam computed tomography image guidance. Using this model, we showed evidence of the early development of region-specific RILD through functional single photon emission computed tomography (SPECT) imaging.