The anti-cancer efficacy of polymeric drug delivery systems is affected by their structures, especially the side chains. In this study, we comparatively examined the potential of -(2-hydroxypropyl)methacrylamide (HPMA)-based and oligo-(ethylene glycol)methacrylate (OEGMA)-based polymeric drug conjugates with doxorubicin (DOX) as efficient anticancer agents. DOX was conjugated to polymers via a pH-sensitive hydrazone bond, and the resulting conjugates pHPMA-DOX (Mw 34 kDa, Rh 10.3 nm) and pOEGMA-DOX (Mw 32 kDa, Rh 9.8 nm) were both synthesized via reversible additionfragmentation chain transfer (RAFT) polymerization with narrow polydispersity indices (1.08 and 1.10, respectively) and they had a similar drug loading content (4.7 and 5.7%, respectively). Compared with pOEGMA-DOX, pHPMA-DOX had a better drug release profile and faster cellular uptake, leading to enhanced cytotoxicity against 4T1 cells. In contrast, the intravenous pharmacokinetics and fluorescence imaging studies suggested that pOEGMA-DOX had a longer blood circulation time of DOX in the body and a greater accumulation of DOX in tumor sites compared with pHPMA-DOX. As for the anti-cancer efficacy of both conjugates in the 4T1 murine breast cancer xenograft model, both conjugates exhibited significantly enhanced therapeutic efficacy compared with free DOX, and without any obvious side effects. Notably, pOEGMA-DOX resulted in higher tumor growth inhibitor (TGI, 80%) than that of pHPMA-DOX (60%). In summary, for the HPMA- and OEGMA-based polymeric conjugates, the side chain of the polymeric carriers showed some differences in physico-chemical characteristics and biological activity, and both polymeric conjugates demonstrated high potential for application as anticancer agents.