Phenylketonuria (PKU), the most common inborn error of metabolism, is an autosomal recessive disorder caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. PAH converts phenylalanine (Phe) to tyrosine (Tyr), and impaired activity of PAH leads to the accumulation of blood Phe to neurotoxic levels. Despite existing dietary and medical treatments, chronic Phe elevations persist in most patients, causing neurological and cognitive deficits, particularly those with the most frequent pathogenic variants, such as c.1222C>T (p.R408W) and c.842C>T (p.P281L). Genome editing has the unique ability to directly correct these pathogenic variants and offers the potential for durable and curative therapies to address the unmet medical needs of PKU patients. Through this work, we have established a pipeline to rapidly screen and optimize prime editing or base editing strategies in vitro and deploy them in vivo with either lipid nanoparticles (LNPs) or adeno-associated viral (AAV) vectors on a timescale of months. We created prime-edited variant-bearing hepatocyte cell lines with the aforementioned PAH variants, and in parallel, humanized PKU mouse models. In homozygous or compound heterozygous PKU mice, we observe complete and long-term durable normalization of blood Phe levels (>90% reduction) as soon as 48 hours after treatment, with whole-liver corrective PAH editing as high as >50% with either prime editing or base editing. We have developed therapeutic leads for R408W and P281L to permanently normalize blood Phe levels and definitively treat PKU in these patients—on track for early-phase clinical trials within a few years. Together, these findings support the development of gene-editing therapies as definitive treatments for PKU and establish a framework for the nomination and validation of base and prime editing therapies for PKU and other hepatic inborn errors of metabolism.