Improved broad-spectrum influenza virus vaccines are desperately needed to provide protection against both drifted seasonal and emerging pandemic influenza A viruses (IAVs). Antibody-based protection from influenza A virus-induced morbidity and mortality is traditionally associated with neutralizing antibodies. As such, vaccine efforts have solely focused on the hemagglutinin (HA) as a vaccine target; however, the HA is mutation prone resulting in the need for annual vaccine reformulation. Broad-spectrum vaccines could be achieved through non-neutralizing antibodies that target conserved influenza virus antigens. Here, we describe six human monoclonal antibodies (mAbs) isolated from two H3N2-infected donors that showed robust binding against the conserved internal nucleoprotein (NP) or matrix protein 1 (M1) of IAV strains. Despite the capacity for potent antigen binding, substantial morbidity was observed in mice prophylactically treated with these mAbs and then challenged with A/Netherlands/602/2009 (H1N1) or A/Switzerland/9715293/2013 (H3N2) viruses. While our findings need to be confirmed with a larger number of mAbs and with polyclonal serum, these findings suggest that human NP and M1 antibodies that are elicited following IAV infection/vaccination do not protect from substantial weight loss in the mouse model and imply that protection afforded targeting these antigens following vaccination/infection is most likely the result of cellular-based immunity.IMPORTANCECurrently, many groups are focusing on isolating both neutralizing and non-neutralizing antibodies to the mutation-prone hemagglutinin as a tool to treat or prevent influenza virus infection. Less is known about the level of protection induced by non-neutralizing antibodies that target conserved internal influenza virus proteins. Such non-neutralizing antibodies could provide an alternative pathway to induce broad cross-reactive protection against multiple influenza virus serotypes and subtypes by partially overcoming influenza virus escape mediated by antigenic drift and shift. Accordingly, more information about the level of protection and potential mechanism(s) of action of non-neutralizing antibodies targeting internal influenza virus proteins could be useful for the design of broadly protective and universal influenza virus vaccines.