Polo-like kinase 1 (PLK1) and bromodomain 4 (BRD4) are well-known oncoproteins that drive tumor cell growth in many cancer types. Simultaneously targeting these protein targets has been intently pursued by scientists to enhance anti-cancer effect in chemotherapy. However, it is rare to design proteolytic targeting chimeras (PROTAC) to degrade these oncoproteins simultaneously by one single molecule. Herein, we designed and synthesized seven PROTAC molecules based on BI-2536, a dual-target inhibitor of BRD4 and PLK1. Among these, compound 17b demonstrated the best ability to degrade PLK1, BRD4 and other BET family proteins. The dual targeting PROTAC 17b induces the almost complete degradation of BET proteins and PLK1 at concentration as low as 3 nM, but proteolysis of PLK1 takes place a lot later than BET proteins (36 h vs 4 h). Compound 17b exhibited strong anti-proliferative activities across multiple cancer cell lines. Furthermore, 17b was able to regulate the expression of downstream genes involved in key cellular processes and exert the prolonged suppression of cancer cell growth. These findings suggest that 17b is a highly potent and efficacious dual-targeting degrader.