Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific protein phosphatase that regulates a variety of synaptic proteins, including NMDA receptors (NAMDRs). To better understand STEP's effect on other receptors, we used mass spectrometry to identify the STEP₆₁ interactome. We identified a number of known interactors, but also ones including the GluA2 subunit of AMPA receptors (AMPARs). We show that STEP₆₁ binds to the C termini of GluA2 and GluA3 as well as endogenous AMPARs in hippocampus. The synaptic expression of GluA2 and GluA3 is increased in STEP-KO mouse brain, and STEP knockdown in hippocampal slices increases AMPAR-mediated synaptic currents. Interestingly, STEP₆₁ overexpression reduces the synaptic expression and synaptic currents of both AMPARs and NMDARs. Furthermore, STEP₆₁ regulation of synaptic AMPARs is mediated by lysosomal degradation. Thus, we report a comprehensive list of STEP₆₁ binding partners, including AMPARs, and reveal a central role for STEP₆₁ in differentially organizing synaptic AMPARs and NMDARs.