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Most Cystic Fibrosis (CF) patients succumb to airway inflammation and pulmonary infections due to <i>Pseudomonas aeruginosa</i>. <i>D</i>-BMAP18, a membrane-permeabilizing antimicrobial peptide composed of D-amino acids, was evaluated as a possible antibacterial aimed to address this issue. The antipseudomonal activity of <i>D</i>-BMAP18 was tested in a pathophysiological context. The peptide displayed activity against CF isolates of <i>Pseudomonas aeruginosa</i> in the presence of CF sputum when combined with sodium chloride and DNase I. In combination with DNase I, <i>D</i>-BMAP18 discouraged the deposition of new biofilm and eradicated preformed biofilms of some <i>P. aeruginosa</i> strains. In addition, <i>D</i>-BMAP18 down regulated the production of TNF-α, IL1-β, and TGF-β in LPS-stimulated or IFN-γ macrophages derived from THP-1 cells indicating an anti-inflammatory activity. The biocompatibility of <i>D</i>-BMAP18 was assessed using four different cell lines, showing that residual cell-specific cytotoxicity at bactericidal concentrations could be abolished by the presence of CF sputum. Overall, this study suggests that <i>D</i>-BMAP18 may be an interesting molecule as a starting point to develop a novel therapeutic agent to simultaneously contrast lung infections and inflammation in CF patients.