The serine/threonine kinase AKT functions as a critical node of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (m-TOR) signaling pathway. Aberrant activation and overexpression of AKT are strongly correlated with numerous human cancers. To date, only two AKT degraders with no structure–activity relationship (SAR) results have been reported. Through extensive SAR studies on various linkers, E3 ligase ligands, and AKT binding moieties, we identified two novel and potent AKT proteolysis targeting chimera (PROTAC) degraders: von Hippel–Lindau (VHL)-recruiting degrader 13 (MS98) and cereblon (CRBN)-recruiting degrader 25 (MS170). These two compounds selectively induced robust AKT protein degradation, inhibited downstream signaling, and suppressed cancer cell proliferation. Moreover, these two degraders exhibited good plasma exposure levels in mice through intraperitoneal injection. Overall, our comprehensive SAR studies led to the discovery of degraders 13 and 25, which are potentially useful chemical tools to investigate biological and pathogenic functions of AKT in vitro and in vivo.