Objectives: Hybrid immunity, resulting from both SARS-CoV-2 infection and COVID-19 vaccination, is well documented to provide broader antibody-mediated protection compared to infection or vaccination alone. While neutralizing antibodies are recognized correlates of protection, the role of Fc-mediated functions such as antibody-dependent cellular cytotoxicity (ADCC) remains poorly defined. This study investigated ADCC responses in UK healthcare workers (HCWs) with varying SARS-CoV-2 exposure histories. Methods: ADCC activity was measured using a Jurkat NFAT reporter cell line expressing CD16, which emits luciferase upon Fc receptor activation by plasma antibodies bound to Spike antigen. Spike-specific IgG1 and IgG3 responses were analysed via automated immunoblotting, and neutralizing capacity was assessed by pseudovirus microneutralization. HCWs were categorized as previously infected before vaccination, naïve-vaccinated (no prior infection), or those with breakthrough infection post-vaccination. Results: Individuals with natural infection prior to immunization showed significantly elevated ADCC compared to naïve-vaccinated individuals. Vaccine-breakthrough infection did not enhance ADCC activity further. In the infection-before-vaccination group, ADCC responses were not significantly influenced by vaccine type, infection severity, age, or gender. Enhanced ADCC correlated with higher levels of Spike-specific IgG1 and IgG3. Principal Component Analysis indicated that IgG1 responses were broadly distributed across all Spike regions, whereas IgG3 responses, especially those targeting the S2 region, contributed distinctively to the observed Fc-mediated activity. Conclusion: These findings highlight that natural infection followed by vaccination drives the most robust ADCC responses in HCWs. IgG1 and IgG3 contribute complementarily to this effect, highlighting the importance of subclass-specific Fc-effector functions in optimizing vaccine-induced immunity.