One of the most critical factors for managing patients with liver disease is inflammation. The liver mediates numerous functions in the innate immunity, these functions predispose the liver to immunity-mediated liver injury if this inflammation is not checked. Models of sterile inflammation-related liver injury have witnessed significant attention during the last 25 years. Understanding the pathophysiology of acute sterile inflammation provides a clear vision about which mechanism is involved in this process. Many studies focused on developing and testing new therapeutic targets on different preclinical models of acute sterile inflammation with an ultimate goal of improving patient outcomes. In this review, we discuss the pathophysiology and the most common in vivo models of sterile inflammation. We then explain the most common innate immune cells that contribute to the development and progression of the disease. Finally, we discuss the interaction between these immune cells and the surrounding “niche" that favors their recruitment to the diseased livers.