Background/Objectives: The correlation between in vivo morphological and functional changes in the degenerating retina in a large animal model of retinitis pigmentosa (RP) has not been characterized longitudinally. Herein, spectral domain optical coherence tomography (SD-OCT) was used to monitor the dynamic morphological changes in the Pro23His rhodopsin transgenic (TgP23H) pig model of RP and was correlated with electroretinography (ERG) in the rapid, early phase of photoreceptor degeneration. Methods: TgP23H and wild-type (WT) hybrid pig littermates at the ages of postnatal days 30 (P30), P60, and P90 were studied. The thickness of different retinal layers was quantified using SD-OCT and compared with histology. Retinal function was evaluated with ERG at corresponding time points. Results: In the WT pigs, retinal morphology on SD-OCT was consistent throughout the observation period. In the TgP23H pigs, the retinal thickness decreased significantly from P30 to P90. Moreover, the relative intensity of the ellipsoid zone (EZ) progressively decreased, while the intensity of the interdigitation zone–retinal pigment epithelium (IZ-RPE) progressively increased during this period. Morphological changes in SD-OCT corresponded with histology, as well as the progressively decreased amplitude of the ERG photopic a- and b-waves in the TgP23H pigs. Conclusions: Retinal degeneration can be quantified using SD-OCT by measuring retinal thickness and the intensity of the EZ and IZ-RPE bands in the TgP23H pig. The SD-OCT results correspond with the histologic and ERG assessments of retinal degeneration. These data provide a foundation for future preclinical studies investigating potential new therapeutic strategies in a large animal model of retinitis pigmentosa.