Abstract Coinfection with pneumococcus during influenza A virus infection is characterized by rapid, uncontrolled bacterial growth, a rebound in viral titers, and a robust inflammatory response. Several factors contribute to influenza-pneumococcal pathogenicity, including aberrant immune responses, tissue destruction, and pathogen strain and dose. By analyzing pathogen kinetics with a mathematical model, we predicted that bacterial establishment and growth is driven by a defect in clearance by alveolar macrophages (AMs), the first line of defense against pneumococcal invasion. This prediction was tested and confirmed in an experimental study, which suggested that these cells are depleted during influenza. Remarkably, both our model prediction and the follow-up experiments agreed that the AM population is reduced by ~85–90% 7d post-influenza infection (pii). Analyzing our coinfection model in more depth allowed us to quantify an initial dose threshold for successful bacterial infection that depends on the level of AM depletion and predict how the threshold changes throughout an influenza virus infection. To validate this prediction, we infected groups of mice with pneumococcus at 1, 3, 5, 7, 9, or 11d pii and at a dose either higher or lower than the predicted threshold. Within 4h after inoculation, bacterial loads decline for doses below the threshold, increase for doses above the threshold, and are dichotomous for doses close to the threshold. These results give insight into the conditions necessary for a secondary bacterial infection to establish during influenza infection and the probability of a successful secondary bacterial infection occurring with seasonal and pandemic influenza virus strains.