A series of novel anaplastic lymphoma kinase (ALK) degraders were designed and synthesized based on proteolysis-targeting chimera (PROTAC) technology by linking two alectinib analogs (<b>36</b> and <b>37</b>) with pomalidomide through linkers of different lengths and types. The most promising degrader <b>17</b> possessed a high ALK-binding affinity and potent antiproliferative activity in the ALK-dependent cell lines and did not exhibit obvious cytotoxicity in ALK fusion-negative cells. More importantly, the efficacy of compound <b>17</b> in a Karpas 299 xenograft mouse model was further evaluated based on its ALK-sustained degradation ability <i>in vivo</i>. The reduction in tumor weight in the compound <b>17</b>-treated group (10 mg/kg/day, I.V.) reached 75.82%, while alectinib reduced tumor weight by 63.82% at a dose of 20 mg/kg/day (P.O.). Taken together, our findings suggest that alectinib-based PROTACs associated with the degradation of ALK may have promising beneficial effects for treating ALK-driven malignancies.