Activated protein C (APC) is an anticoagulant with potent cytoprotective and anti-inflammatory effects. K150del, a natural variant of APC, is associated with reduced anticoagulant activity. We performed a comprehensive study to analyze the functional alterations of the K150del mutant. Transcriptome analysis of HEK 293T cells treated with wild and mutant APC revealed differentially expressed genes enriched in inflammatory, apoptotic, and virus defense-related signaling pathways. Both wild and mutant APC displayed concentration-dependent cytoprotective effects. Low concentrations of K150del mutant resulted in decreased anti-inflammatory and anti-apoptotic activities, whereas its higher concentrations restored these effects. Expression of virus defense-related genes improved in mouse lung tissues after repeated administration of the APC variant. These results suggest that the APC K150del mutant could help clinicians to accurately predict disease risks and serve as a potential auxiliary therapeutic in viral infections, including 2019 coronavirus disease (COVID-19).