Patients with hematologic malignancies (HM) are highly susceptible to bloodstream infection (BSI), particularly those undergoing treatments such as chemotherapy. A common and debilitating side effect of chemotherapy is oral and intestinal mucositis. These Patients are also at high risk of developing sepsis, which can arise from mucosal barrier injuries and significantly increases mortality in these patients. While conventional antibiotics are effective, their use can lead to antimicrobial resistance (AMR) and disrupt the gut microbiota (dysbiosis). In this review, we discuss utilizing host defense peptides (HDPs), key components of the innate immune system, and immune system inducers (ISIs) to maintain mucosal barrier integrity against infection, an underexplored host-directed therapy (HDT) approach to prevent BSI and sepsis. We advocate for the discovery of potent and safe ISIs for clinical use and call for further research into the mechanisms by which these ISIs induce HDPs and strengthen mucosal barriers.