Tissue-resident alveolar macrophage (TR-AM) depletion is a key event upon influenza A virus (IAV)-induced pneumonia. However, the mechanisms behind it remain largely unknown. We found that significant decrease in TR-AM numbers begins on d3 post-infection (pi), as shown by flow cytometry analysis. Gene expression analysis of flow-sorted TR-AM revealed tumor necrosis factor superfamily receptor 14 (tnfrsf14) as one of the highest upregulated genes upon infection. At the same time, the tnfsf14 ligand was highly expressed in the BAL of infected mice, but also in the BAL of patients with severe H1N1 pneumonia. Interestingly enough, tnfsf14-/- mice and wt mice treated with an anti-tnfsf14 antibody retained intact TR-AM numbers over the infection course, compared to their respective controls. In addition to that, lack of tnfsf14 through genetic deletion or antibody blocking resulted in an improved clinical outcome upon post-viral pneumococcal infection. Single-cell sequencing analysis of flow-sorted lung leukocytes revealed neutrophils as the main cellular source of tnfsf14 and neutrophil depletion led to an attenuated TR-AM loss. With two possible receptors for tnfsf14, tnfsf14 and lymphotoxin beta receptor (ltβr), we sought to investigate which one was responsible for driving tnfsf14 effects during IAV infection. We identified ltβr as the main tnfsf14-associated receptor inducing TR-AM death, as ltβr-/- mice presented an attenuated macrophage loss and improved clinical scoring following IAV infection, compared to tnfrsf14-/- mice. Our data thus indicates that targeting tnfsf14 can improve the compromised host defense following IAV infection.