Acinetobacter baumannii is a critical emerging bacterial pathogen. The organism is commonly resistant to multiple antimicrobials and is associated with severe infections, such as ventilator-associated pneumonia (VAP), in healthcare settings. A. baumannii resides in environmental reservoirs; however, the conditions which induce pathogenicity and trigger A. baumannii to activate its virulence pathways during infection are poorly understood. To understand how A. baumannii interacts with the host environment, we created an in vitro model, aiming to mimic physiological conditions during VAP. We investigated how serum albumin, heme, reductant, and the host lipid degradation product lysophosphatidylcholine (LPC) impact the growth of clinical A. baumannii isolates isolated from the bronchoalveolar lavage fluid of VAP patients and compared them to the laboratory reference strain ATCC17978. Our findings show that the presence of serum albumin and LPC improved the growth of A. baumannii substantially, suggesting that the success of A. baumannii in extra-environmental niches may be limited by lipid availability. The addition of heme increased the growth of A. baumannii clinical isolates by ~40%, a finding not observed with ATCC17978. Notably, while the presence of reductant promoted the growth of ATCC17978, clinical isolates exhibited more variable responses, including major, minor, and no noticeable growth defects. We next assessed the antimicrobial susceptibility of the clinical A. baumannii in this in vitro system, which resulted in significantly increased tolerance against the β-lactam antimicrobial meropenem compared to standard testing conditions. Furthermore, we observed low, yet persistent, growth in the presence of meropenem that was absent in standard susceptibility media. Our data suggest that the clinical isolates are better adapted to the local redox conditions within the niches from which they were isolated, and may have better tolerance to last-resort antimicrobials than previously thought. We conclude that exposing such bacterial pathogens to more physiological “host-like” environments unravels new processes relevant to pathogenesis and questions current clinical management strategies.