Perioperative Neurocognitive Disorders are complications that mostly affect elderly surgical patients and those with existing cognitive impairment. The pathogenic mechanisms involve activation of the innate immune response that cause a neuroinflammatory reaction that downregulates synaptic plasticity, the neurobiological basis for learning and memory. Neural and humoral mechanisms usually resolve the inflammation; however, resolution may be incomplete resulting in persistent neuroinflammation and cognitive decline. Recently, the pleotropic interleukin-6 (IL-6) has been identified as necessary and sufficient for producing PNDs and could be a druggable target; however, blocking IL-6’s neurotoxic action may also prevent its regenerative properties that are required for healing. The IL-6 signaling pathways for regeneration are mediated by classic signaling initiated by IL-6 binding to a limited populations of cells that express membrane-bound IL-6 receptors. The neurotoxic properties are transduced by trans-signaling in which IL-6 binds to soluble IL-6 receptors (sIL-6R) that are shed by the action of proteolytic enzymes. Selective blockade of IL-6 trans-signaling with sgp130Fc prevents PNDs without interfering with healing; olamkicept, a pharmaceutical formulation of this blocker, is undergoing clinical trials for treatment of another IL-6 trans-signaling-mediated disease, inflammatory bowel disease (IBD). If safe and effective for IBDs, olamkicept could be repurposed for the prevention and/or treatment of PNDs and possibly other neuroinflammation-associated neurodegenerative conditions.