Klebsiella pneumoniaecan cause widespread infections and is an important factor of hospital- and community-acquired pneumonia. The emergence of hypervirulentK. pneumoniaeposes a serious clinical therapeutic challenge and is associated with a high mortality. The goal of this work was to investigate the influence ofK. pneumoniaeinfection on host cells, particularly pyroptosis, apoptosis, and autophagy in the context of host–pathogen interactions to better understand the pathogenic mechanism ofK. pneumoniae. Two clinicalK. pneumoniaeisolates, one classicalK. pneumoniaeisolate and one hypervirulentK. pneumoniaeisolate, were used to infect RAW264.7 cells to establish anin vitroinfection model. We first examined the phagocytosis of macrophages infected withK. pneumoniae. Lactate dehydrogenase (LDH) release test, and calcein-AM/PI double staining was conducted to determine the viability of macrophages. The inflammatory response was evaluated by measuring the pro-inflammatory cytokines and reactive oxygen species (ROS) production. The occurrence of pyroptosis, apoptosis, and autophagy was assessed by detecting the mRNA and protein levels of the corresponding biochemical markers. In addition, mouse pneumonia models were constructed by intratracheal instillation ofK. pneumoniaeforin vivovalidation experiments. As for results, hypervirulentK. pneumoniaewas much more resistant to macrophage-mediated phagocytosis but caused more severe cellular damage and lung tissues damage compared with classicalK. pneumoniae. Moreover, we found increased expression of NLRP3, ASC, caspase-1, and GSDMD associated with pyroptosis in macrophages and lung tissues, and the levels were much higher following hypervirulentK. pneumoniaechallenge. Both strains induced apoptosisin vitroandin vivo; the higher apoptosis proportion was observed in infection caused by hypervirulentK. pneumoniae. Furthermore, classicalK. pneumoniaestrongly triggered autophagy, while hypervirulentK. pneumoniaeweakly activated this process. These findings provide novel insights into the pathogenesis ofK. pneumoniaeand may form the foundation for the future design of treatments forK. pneumoniaeinfection.