Significance Rift Valley fever virus (RVFV)–specific monoclonal antibodies from survivors of natural infection and vaccination were isolated to understand how RVFV is targeted for neutralization by the human immune system. These antibodies bind to specific regions of the viral surface, some of which are complex quaternary epitopes, and they block RVFV infection at extremely low concentrations. A new mechanism by which these mAbs can neutralize RVFV is described whereby the antibody may prevent necessary structural rearrangements in the viral proteins for infection. The antibodies isolated here have potential use in pre-exposure prophylaxis or post-exposure therapy against RVFV infection and should be studied further in that context.