During the course of Lyme disease, humans mount a robust and sustained antibody response against dozens of Borrelia burgdorferi outer surface lipoproteins. Identifying which antibodies are associated with spirochete clearance and disease resolution is of paramount importance in therapeutic development. In this study, we describe the isolation and structural characterization of a human monoclonal antibody (MAb) against decorin binding protein A (DbpA), one of the most immunogenic of B. burgdorferi’s outer surface proteins. High-resolution epitope mapping by HX-MS and X-ray crystallography revealed that F945 associates with a lateral face of DbpA in a side-on orientation without obstructing resides associated with DbpA’s ability to bind components of the extracellular matrix. The structure of the DbpA-F945 Fab complex revealed an outsized role for variable light chain (V L ) germline encoded residues in mediating DbpA interactions. In fact, the majority of the critical contacts between F945 and DbpA involved V k 1- 33 germline encoded residues, suggesting that certain human B cell receptors (BCR) may be preconfigured to recognize DbpA and therefore have a lower the threshold for B cell activation and clonal development. Passive administration of F945 IgG was not sufficient to protect against B. burgdorferi in a mouse model of needle infection, although a role for F945 in influencing B. burgdorferi tissue tropism or retention within specific niches cannot be ruled out. Collectively these results provide the first structural insight into human antibody response to DbpA with implications for understanding factors involved in disease resolution.