In this study, synthetic mimics of antimicrobial peptides based on poly(oxanorbornene) molecules (or PONs) were used to coat CdTe quantum dots (QDs). These PONs-CdTe QDs were investigated for their activity against Escherichia coli, a bacterium with antibiotic resistant strains. At the same time, the antibacterial activity of the PONs-CdTe QDs was compared to the antibacterial activity of free PONs and free CdTe QDs. The observed antibacterial activity of the PONs-CdTe QDs was additive and concentration dependent. The conjugates had a significantly lower minimum inhibitory concentration (MIC) than the free PONs and QDs, particularly for PONs-CdTe QDs which contained PONs of high amine density. The maximum activity of PONs-CdTe QDs was not realized by conjugating PONs with the highest intrinsic antibacterial activity (i.e., the lowest MIC in solution as free PONs), indicating that the mechanism of action for free PONs and PONs-CdTe QDs is different. Equally important, conjugating PONs to CdTe QDs decreased their hemolytic activity against red blood cells compared to free PONs, lending to higher therapeutic indices against E. coli. This could potentially enable the use of higher, and therefore more effective, PONs-QDs concentrations when addressing bacterial contamination, without concerns of adverse impacts on mammalian cells and organisms.