Objectives: Retinitis pigmentosa (RP) is commonly initiated by rod photoreceptor degeneration due to genetic mutations, followed by secondary cone loss and progressive blindness. Preserving rod function during the earlier stages of RP is a key therapeutic goal, as rod survival supports cone maintenance and delays vision loss. In this study, we investigated the therapeutic potential of transient knockdown of retinoid-related orphan receptor beta (RORB) using a cell-penetrating asymmetric small interfering RNA (cp-asiRORB) in Rho^P23H mice, a model of autosomal dominant RP. While the role of RORB in the adult retina remains unclear, prior studies of related nuclear receptors suggest potential involvement in proteostasis. Based on this, we hypothesized that persistent RORB expression may influence photoreceptor homeostasis under degenerative stress. Methods: We first optimized the cp-asiRORB design to enhance gene silencing and cellular uptake. In vitro studies were conducted under proteotoxic stress. In vivo studies involved intravitreal administration of cp-asiRORB in Rho^P23H mice. Furthermore, single-cell RNA sequencing of rod photoreceptors was performed. Results: In vitro studies demonstrated that RORB knockdown improved cell viability, reduced apoptosis, and diminished aggresome formation under proteotoxic stress. Intravitreal administration of cp-asiRORB in Rho^P23H mice effectively reduced RORB expression in the retina, leading to improved photoreceptor survival and preserved visual function. Single-cell RNA sequencing revealed upregulation of proteasomal subunit genes in cp-asiRORB-treated eyes, indicating enhanced proteostasis. Conclusions: Together, these results demonstrate that transient suppression of RORB mitigates proteotoxic stress and slows RP progression, highlighting a novel RNAi-based therapeutic strategy for retinal degeneration.