Multi-domain signaling enzymes are often regulated through extensive inter-domain interactions, and disruption of inter-domain interfaces by mutations can lead to aberrant signaling and diseases. For example, the tyrosine phosphatase SHP2 contains two phosphotyrosine recognition domains that auto-inhibit its catalytic domain. SHP2 is canonically activated by binding of these non-catalytic domains to phosphoproteins, which destabilizes its auto-inhibited state, and several mutations at the main auto-inhibitory interface have been shown to hyperactivate SHP2 in cancers and developmental disorders. Hundreds of clinically observed mutations in SHP2 have not been characterized, but their locations suggest alternative modes of dysregulation. Here, we perform deep mutational scanning on full-length SHP2 and the isolated phosphatase domain to dissect mechanisms of dysregulation. Our analysis reveals mechanistically diverse mutational effects and identifies key intra- and inter-domain interactions that contribute to SHP2 activity, dynamics, and regulation. Our datasets also provide insights into the potential pathogenicity of previously uncharacterized clinical variants.