Pseudomonas aeruginosadominates the complex polymicrobial cystic fibrosis (CF) airway and is a leading cause of death in persons with CF. Interestingly, oral streptococcal colonization has been associated with stable CF lung function. The most abundant streptococcal species found in stable patients,Streptococcus salivarius, has been shown to downregulate pro-inflammatory cytokines in multiple colonization models. However, no studies have demonstrated howS. salivariuspotentially improves lung function. Our lab previously demonstrated that theP. aeruginosaexopolysaccharide Psl promotesS. salivariusbiofilm formationin vitro, suggesting a possible mechanism by whichS. salivariusis incorporated into the CF airway microbial community. In this study, we demonstrate that co-infection of rats leads to enhancedS. salivariuscolonization and reducedP. aeruginosacolonization. Histological scores for tissue inflammation and damage are lower in dual-infected rats compared toP. aeruginosainfected rats. Additionally, pro-inflammatory cytokines IL-1β, IL-6, CXCL2, and TNF-α are downregulated during co-infection compared toP. aeruginosasingle-infection. Lastly, RNA sequencing of cultures grown in synthetic CF sputum revealed thatP. aeruginosaglucose metabolism genes are downregulated in the presence ofS. salivarius, suggesting a potential alteration inP. aeruginosafitness during co-culture. Overall, our data support a model in whichS. salivariuscolonization is promoted during co-infection withP. aeruginosa, whereasP. aeruginosaairway bacterial burden is reduced, leading to an attenuated host inflammatory response.