Purpose <p>Inhalable liquid formulation of endolysins represents a promising alternative to conventional antibiotics. Dry powder formulations offer improved stability for endolysin pulmonary delivery. This study aimed to evaluate the efficacy of an inhalable dry powder or liquid formulation of endolysin Cpl-1 alone and to compare it with liquid combinations of Cpl-1 with either gentamicin or endolysin Pal in a murine model of <i>S. pneumoniae</i> lung infection.</p> Methods <p>A dry powder formulation of Cpl-1 was produced via spray drying, while liquid formulations were prepared by dissolving Cpl-1, or in combination with gentamicin or endolysin Pal in liquid. The droplet size distribution of aerosolized formulations was also characterized. Mice were intratracheally infected with <i>S. pneumoniae</i> and treated with either powder or liquid formulations. The bacterial load in respiratory system was assessed 26&#xa0;h post-infection. The stability and activity of Cpl-1 in BALF were also evaluated <i>ex vivo</i>.</p> Results <p>A single dose of Cpl-1 powder formulation or Cpl-1 liquid formulation (40&#xa0;µg/mouse) reduced pulmonary bacterial load by approximately 1 log₁₀. Importantly, the combination of Cpl-1 and Pal in liquid form resulted in a synergistic 2.0 log₁₀ reduction, significantly greater than either endolysin alone, while combining Cpl-1 with gentamicin did not enhance antibacterial activity. <i>Ex vivo</i> assays confirmed that Cpl-1 retained full enzymatic activity after incubation in BALF.</p> Conclusion <p>This proof-of-principle study demonstrated that inhalable endolysin liquid and powder formulations could potentially be used to treat bacterial lung infections. Moreover, the combination of multiple endolysins could increase antimicrobial activity over endolysin monotherapy.</p>