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. Vaccine studies have focused on the induction of neutralising antibodies that target cell-free virus spread, 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 have investigated the capacity of monoclonal antibodies (mAbs) to bind infected cells and activate NK-dependent antibody-dependent cellular cytotoxicity (ADCC). Despite encoding immune-evasins, HCMV infected cells were susceptible to ADCC. Profiling of the infected cell-surface via quantitative proteomics identified 15 non-structural viral proteins expressed during early stages of 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. However, using a mix of mAbs might be difficult to translate into the clinic. To reduce the number of mAbs required, they were converted into antibody-like constructs, including Redirected Optimised Cell Killers (ROCKs) and Antibody-based NK-cell Engager Therapeutics (ANKETs^TM), which contained enhancements to improve binding with, proliferation and activation of, NK cells. The ANKET^TM platform has been used to generate successful anti-cancer constructs; however, although anti-HCMV ANKETs^TM led to ADCC against cells expressing UL141 from a vector, they were unable to drive significant ADCC against HCMV. In comparison, ROCKs mediated ADCC as single constructs and strongly controlled virus spread at concentrations 100-times lower than pooled polyclonal anti-HCMV IgGs. This reveals a novel immunotherapeutic approach against HCMV and demonstrates ways of maximising antiviral activity by exploiting engineered antibody-like molecules.