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It is rapidly degraded after nerve injury, promoting axon degeneration. However, the mechanisms regulating NMNAT2 ubiquitination and turnover in neurons remain unclear. In this study, we identify the F-box protein FBXO21 as an NMNAT2-binding protein, and its deficiency confers axonal protection via increasing NMNAT2 abundance. FBXO21 recruits SKP1, CUL1, and RBX1 to form an SCFFBXO21 complex, which promotes NMNAT2 ubiquitination in vivo and in vitro. SCFFBXO21 ubiquitinates NMNAT2 at K155 within an isoform-specific targeting and interaction domain of the family of NMNATs, which underlies the unique labile nature of NMNAT2. The ubiquitination-deficient NMNAT2-K155R exhibits substantially reduced protein turnover and enhanced axon-protective capacity. Finally, in Fbxo21 knockout mice, NMNAT2 levels are markedly increased and the survival of injured sciatic nerves is significantly prolonged. 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