Human Cytomegalovirus (HCMV) can result in severe disease in immunocompromised individuals and following congenital infection. Therapeutics are limited by virus resistance and undesirable side effects, and despite many trials no vaccines are licensed. Vaccines have focused on the induction of neutralising antibodies targeting cell-free virus, however HCMV spreads cell-to-cell within the host, limiting the efficacy of this response. There is therefore a need for strategies targeting the infected cell directly. We investigated the capacity of monoclonal antibodies (mAbs) to bind infected cells and activate NK-mediated antibody-dependent cellular cytotoxicity (ADCC). Despite encoding immune-evasins, infected cells were susceptible to ADCC. Quantitative proteomics profiling of the infected cell-surface identified 15 non-structural viral proteins expressed early during infection, of which five activated ADCC. Human mAbs targeting one of these antigens efficiently controlled virus spread through ADCC, when used as a mix of 5 against multiple epitopes. To reduce the number of mAbs required they were converted into antibody-like constructs termed Redirected Optimised Cell Killers (ROCKs), which contain enhancements designed to improve binding with, proliferation, and activation of, NK cells. ROCKs mediated ADCC as single molecules and strongly controlled virus spread at concentrations 100-times lower than natural IgG. Confocal microscopy revealed that ROCKs enhanced convergence of NK lytic granules to the MTOC and polarisation towards target cells, while TIRF microscopy showed a significant enhancement of CD16 clustering at the NK immune synapse.   This indicates a novel immunotherapeutic approach against HCMV and demonstrates ways of maximising NK cell antiviral activity through engineering of antibody-like molecules.