Rheumatoid arthritis (RA) is associated with elevated levels of a numerous acute phase proteins (APPs), including lipocalin 2 (Lcn2), that drive/dampen the inflammatory response. Lcn2, a 25KDa innate immune protein is known to be significantly up regulated during various inflammatory disorders including antibody-mediated arthritis such as rheumatoid arthritis (RA). However, its biological role remains unclear. Herein we have demonstrated that Lcn2 levels were significantly upregulated during collagen antibody induced arthritis (CAIA). Lcn2-knockout mice (Lcn2KO) developed more severe serum-induced arthritis compared to wild-type (WT) mice. Histological analysis revealed extensive tissue and bone destruction in Lcn2KO mice compared to WT mice. Furthermore, we have observed reduced immune cell infiltration in Lcn2KO mice compared to WT mice. These studies suggest a crucial role of Lcn2 in resolution of arthritic inflammation, making it a promising target in designing better therapeutic strategies for the treatment of rheumatoid arthritis.