Design and synthesis of novel water-soluble polymers bearing reactive side chains are actively pursued due to their increasing demand in areas such as bioconjugation and drug delivery. This study reports the fabrication of poly(ethylene glycol) methacrylate based thiol-reactive water-soluble polymeric supports that can serve as targeted drug delivery vehicles. Thiol-reactive maleimide units were incorporated into polymers as side chains by use of a furan-protected maleimide containing monomer. Atom transfer radical polymerization (ATRP) was employed to obtain a family of well-defined copolymers with narrow molecular weight distributions. After the polymerization, the maleimide groups were activated to their reactive form, ready for conjugation with thiol-containing molecules. Efficient functionalization of the maleimide moieties was demonstrated by conjugation of a tripeptide glutathione under mild and reagent-free aqueous conditions. Additionally, hydrophobic thiol-containing dye (Bodipy-SH) and a cyclic peptide-based targeting group (cRGDfC) were sequentially appended onto the maleimide bearing polymers to demonstrate their efficient multifunctionalization. The conjugates were utilized for in vitro experiments over both cancerous and healthy breast cell lines. Obtained results demonstrate that the conjugates were nontoxic, and displayed efficient cellular uptake. The presence of the peptide based targeting group had a clear effect on increasing the uptake of the dye-conjugated polymers into cells when compared to the construct devoid of the peptide. Overall, the facile synthesis and highly efficient multifunctionalization of maleimide-containing thiol-reactive copolymers offer a novel and attractive class of polyethylene glycol-based water-soluble supports for drug delivery.