Over the past 20 years natural killer (NK) cell-mediated immunotherapies have emerged as a safe and effective treatment approach for advanced leukaemia. The importance of an appropriate pre-activation strategy has been highlighted as a major determinant of therapeutic success for adoptive NK cell therapies, with common approaches leveraging proinflammatory cytokines to boost NK cell activity in vivo. The type I interferon (IFN) family are well-known for their ability to activate NK cells against malignant cells; though IFN⍺2 is currently the only subtype approved for the treatment of cancer. Indeed, the capacity for individual subtypes to enhance NK cell anti-cancer activity remains unexplored. We investigated the potential for the 12 IFN⍺ subtypes and IFNβ to enhance the anti-leukaemic activity of healthy donor-derived NK cells. A systematic screen was carried out to identify which IFN subtype(s) harboured the greatest potential to stimulate NK cell degranulation and cytokine production against the leukaemic cell line K562. Interestingly, several IFN subtypes significantly enhanced NK cell activity against K562 targets over IFN⍺2. Specifically, IFN⍺14 and IFNβ were identified as superior activators of NK cell effector function in vitro. To test the ability of these subtypes to enhance NK cell activity in vivo, IFN stimulation was overlaid onto a standard adoptive NK cell therapy protocol. Strikingly, mice that received NK cells pre-activated with IFN⍺14, but not IFNβ, experienced significantly prolonged survival compared to those that received standard NK cell therapy. These results highlight the differential potencies of individual IFN subtypes and support further investigations into their use in future immunotherapies.