Despite the recent success of gene‐based complementation approaches for genetic recessive traits, the development of therapeutic strategies for gain‐of‐function mutations poses great challenges. General therapeutic principles to correct these genetic defects mostly rely on post‐transcriptional gene regulation (RNA silencing). Engineered zinc‐finger (ZF) protein‐based repression of transcription may represent a novel approach for treating gain‐of‐function mutations, although proof‐of‐concept of this use is still lacking. Here, we generated a series of transcriptional repressors to silence human rhodopsin (hRHO), the gene most abundantly expressed in retinal photoreceptors. The strategy was designed to suppress both the mutated and the wild‐type hRHO allele in a mutational‐independent fashion, to overcome mutational heterogeneity of autosomal dominant retinitis pigmentosa due to hRHO mutations. Here we demonstrate that ZF proteins promote a robust transcriptional repression of hRHO in a transgenic mouse model of autosomal dominant retinitis pigmentosa. Furthermore, we show that specifically decreasing the mutated human RHO transcript in conjunction with unaltered expression of the endogenous murine Rho gene results in amelioration of disease progression, as demonstrated by significant improvements in retinal morphology and function. This zinc‐finger‐based mutation‐independent approach paves the way towards a ‘repression–replacement’ strategy, which is expected to facilitate widespread applications in the development of novel therapeutics for a variety of disorders that are due to gain‐of‐function mutations.