The clinical success of CRISPR therapies is dependent on the safety and efficacy of Cas proteins. The Cas9 from Francisella novicida (FnCas9) has negligible affinity for mismatched substrates enabling it to discriminate off-targets in DNA with very high precision even at the level of binding. However, its cellular targeting efficiency is low, limiting its use in therapeutic applications. Here, we rationally engineer the protein to develop enhanced (enFnCas9) variants and expand its cellular editing activity to genomic loci previously inaccessible. Notably, some of the variants release the protospacer adjacent motif (PAM) constraint from NGG to NGR/NRG making them rank just below SpCas9-RY and SpCas9-NG in their accessibility across human genomic sites. The enFnCas9 proteins, similar to Cas12a and Cas12f, harbor high intrinsic specificity and can diagnose single nucleotide variants accurately. Importantly, they provide superior outcomes in terms of editing efficiency, knock-in rates, and off-target specificity over other engineered high-fidelity versions of SpCas9 (SpCas9-HF1 and eSpCas9). Broad targeting range coupled with remarkable specificity of DNA interrogation underscores the utility of these variants for safe and efficient therapeutic gene correction across multiple cell lines and target loci.