Sleep is characterized by a specific regulation of cortical circuits that enables plasticity underlying memory consolidation. Vasoactive intestinal polypeptide (VIP)-positive interneurons exert high-level control over cortical activity by inhibiting parvalbumin (PV) and somatostatin (SST)-positive interneurons, thereby disinhibiting pyramidal cells. We used in vivo two-photon Ca2+ imaging to quantify the activity of layer 2/3 VIP interneurons in naturally sleeping male mice during wake, slow-wave sleep (SWS), and rapid-eye-movement (REM) sleep, as well as during spindles and slow oscillations (SOs). VIP activity was lowest during SWS and acutely upregulated during spindles and SOs, presumably facilitating memory processing in cortical circuits. Notably, across all states, VIP activity showed a profound ∼0.02-Hz infraslow rhythm, which, during SWS epochs, was inversely phase-coupled to the infraslow rhythm of spindle activity. In contrast, such coupling was absent in SST and PV interneurons, suggesting that VIP cells uniquely regulate infraslow spindle-related dynamics within cortical circuits.