Yellow fever virus (YFV) is a mosquito-borne flavivirus that causes severe hepatic disease and mortality in humans. Despite the successful creation of the live-attenuated YFV-17D vaccine in 1937, a significant number of YFV infections are still reported annually. The situation is further exacerbated by the lack of approved therapeutics. In this study, we reveal the epitope of a monoclonal antibody (mAb) with promising therapeutic potential via cryogenic electron microscopy (cryo-EM). The mAb, designated CS45, demonstrates remarkable cross-neutralising capabilities against both vaccine and virulent strains of YFV, as well as related flaviviruses including Wesselsbron virus (WSLV), Sepik virus (SEPV), and dengue virus serotype 2 (DENV2). Notably, CS45 offers protection from lethal DENV2 challenge in an interferon-α/β receptor-deficient mice model, underscoring its therapeutic potential. To elucidate the structural basis of CS45's cross-neutralising activity, we generated CS45 as an antigen-binding fragment (Fab) and complexed it with chimeric virion particles of YFV17D-204, SEPV, and WSLV. These complexes were then imaged via cryo-EM. Through single particle analysis, we resolved the asymmetric units of YFV17D-204, SEPV, and WSLV in complex with CS45 Fab to resolutions of 4.0 Å, 4.1 Å, and 4.3 Å, respectively. Atomic modelling of the Fab-envelope protein interface revealed that CS45's epitope is located in the DI-DIII linker region of the envelope protein. This epitope represents a novel cross-reactive target and holds significant potential for the development of cross-reactive therapeutic antibodies and can inform epitope-based vaccine design.