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Bacteriophages and phage enzymes are considered as possible alternatives to antibiotics in the treatment of infections caused by antibiotic-resistant bacteria. Due to the ability to cleave the capsular polysaccharides (CPS), one of the main virulence factors of <i>Klebsiella pneumoniae</i>, phage depolymerases, has potential in the treatment of <i>K. pneumoniae</i> infections. Here, we characterized in vivo two novel phage-encoded polysaccharide depolymerases as therapeutics against clinical isolates of <i>K. pneumoniae</i>. The depolymerases Dep_kpv79 and Dep_kpv767 encoded by Klebsiella phages KpV79 (Myoviridae; Jedunavirus) and KpV767 (Autographiviridae, Studiervirinae, Przondovirus), respectively, were identified as specific β-galactosidases that cleave the <i>K. pneumoniae</i> K57 type CPS by the hydrolytic mechanism. They were found to be highly effective at combating sepsis and hip infection caused by <i>K. pneumoniae</i> in lethal mouse models. Here, 80–100% of animals were protected against death by a single dose (e.g., 50 μg/mouse) of the enzyme injected 0.5 h after infection by <i>K. pneumoniae</i> strains of the K57 capsular type. The therapeutic effect of the depolymerases is because they strip the capsule and expose the underlying bacterium to the immune attack such as complement-mediated killing. These data provide one more confirmation that phage polysaccharide depolymerases represent a promising tool for antimicrobial therapy.