Human cytomegalovirus (HCMV), a ubiquitous betaherpesvirus, infects ~60% of adults in developed countries and over 90% in developing regions. While typically asymptomatic in immunocompetent individuals, HCMV poses significant risks including end-organ disease and mortality for immunocompromised and immunologically immature populations such as transplant recipients, individuals with HIV and congenitally infected neonates. Current antivirals are limited by toxicity, resistance and suboptimal efficacy. One solution to limit toxicity of antivirals is to target it specifically against the infected cells. Thus our aim is to develop a biocompatible, cell-targeted antiviral platform using ultrasound-activated piezoelectric-antibody conjugates capable of selectively disrupting HCMV-infected cells.  These conjugates harness the properties of piezoelectric nanoparticles, generating localized electric fields upon ultrasound stimulation. When conjugated to anti-HCMV antibodies directed against viral antigens expressed on the cell surface they enable precise targeted, externally triggered antiviral activity. As proof of principle, we demonstrate a conjugated antibody directed against the AD-6 domain of glycoprotein B resulted in a reduction in cell-associated viral spread by up to 91% at micromolar to nanomolar concentrations, outperforming unconjugated AD-6 antibody by a factor of up to ~4,000. Importantly, inactivated conjugates preserved >93–100% cell viability, underscoring a unique switchable mechanism of action that circumvents general toxicity. This is the first demonstration of piezoelectric-antibody conjugates as a therapeutic antiviral modality, offering a switchable, targeted, and biocompatible strategy against HCMV. Clearly, this platform holds promise for broader application to functionalize antibodies directed against any viral antigen expressed at the plasma membrane including those associated with latent infection.