Cytomegalovirus (CMV) can be reactivated in patients with acute respiratory distress syndrome (ARDS), a condition associated with poor prognosis. However, the biological characteristics of CMV reactivation remain unclear. Here we built a multi-omics profiling database using blood plasma and bronchoalveolar lavage fluid (BALF) from 151 ARDS cohort, with 47 in CMV reactivation group and 104 in no reactivation group. Proteomic analyses revealed suppression of immune, complement, and ribosomal subunit biogenesis pathways in BALF, along with activation of immune responses in plasma. Metabolomic analyses demonstrated significant upregulation of tryptophan metabolism in plasma and pyrimidine metabolism in BALF. Several biomarkers linked to host immune responses and viral replication were correlated with increased mortality. Finally, our analysis presented that distinct host protein expression and metabolic alterations in different sample types from patients with CMV reactivation may contribute to poor prognosis. These findings provide new insights into the impact of CMV reactivation in ARDS patients.