Clathrate hydrates have received massive attention because of their potential application as energy storage materials. Host water frameworks of clathrate hydrates provide empty cavities that can capture not only small molecular guests but also radical species induced by γ-irradiation. In this work, we investigated structure II methyl vinyl ketone (MVK) binary clathrate hydrates with CH4, O2, and N2 and the effects of secondary guest species on MVK conformation in the cavity of hydrate and on the thermodynamic stability of unirradiated and γ-irradiated hydrate phases. The present findings provide meaningful information to understand the nature of guest-host interactions in γ-irradiated clathrate hydrates and to open up practical applications for hydrate-based nanoreactors.