Inducing cell ferroptosis by inactivating glutathione peroxidase 4 (GPX4) is a popular cancer treatment strategy. However, only few GPX4 inhibitors have been developed to date. PROteolysis Targeting Chimera (PROTAC) is a promising approach to provide new opportunities to overcome limitations of traditional therapeutics. Herein, a PROTAC-like activity-based probe PD-Q2 was first assembled using Ugi reaction, consisting of a known GPX4 inhibitor ML-162 homolog to the E3 ligase cereblon ligand-pomalidomide. Pull-down and immunoblotting analysis revealed that GPX4 was a covalent target of PD-Q2, but the degradation efficiency was weak. Therefore, a series of degraders was further synthesized by varying the linkers of heterofunctional PROTACs. Among these degraders, PD-4 and PD-P2 were found to promote effective GPX4 degradation via the ubiquitin–proteasome system and cause lipid ROS accumulation. PD-4 and PD-P2 showed potent inhibitory of colony formation and cell growth. Furthermore, we found that with pomalidomide, the degraders exhibit a high fluorescent signal that is mostly localized in the lysosome, which may affect the effectiveness of anti-cell proliferation. Overall, we provide GPX4 degraders for further exploring therapeutic potential of regulating ferroptosis.