•  The medial prefrontal cortex (mPFC) is often referred to as the ‘visceral cortex’, largely based on anatomical connections and cardiovascular influences. •  Although an extensive network of inhibitory interneurons regulates PFC function, their roles in modifying central respiratory, metabolic and cardiac functions have not been explored. •  This study provides the first integrative investigation describing central respiratory, metabolic and cardiac variables altered following chemical disinhibition of discrete subregions of the mPFC. •  Changes were evoked in a site‐dependent manner, with central respiratory function modified throughout the mPFC, and exclusively from dorsal regions. By contrast, central respiratory, metabolic and cardiac functions were simultaneously increased in the ventral mPFC, particularly the infralimbic cortex. •  These data provide reference material for future investigations into chronic changes in the activity of neurons within the mPFC, as seen in stress and mental health disorders, which are often accompanied by autonomic and respiratory dysfunction. Abstract  The prefrontal cortex (PFC) is referred to as the visceral motor cortex; however, little is known about whether this region influences respiratory or metabolic outflows. The aim of this study was to describe simultaneous changes in respiratory, metabolic and cardiovascular functions evoked by disinhibition of the medial PFC (mPFC) and adjacent lateral septal nucleus (LSN). In urethane‐anaesthetized rats, bicuculline methiodide was microinjected (2 mm; GABA‐A receptor antagonist) into 90 sites in the mPFC at 0.72–4.00 mm from bregma. Phrenic nerve amplitude and frequency, arterial pressure, heart rate, splanchnic and lumbar sympathetic nerve activities (SNA), expired CO2, and core and brown adipose tissue temperatures were measured. Novel findings included disturbances to respiratory rhythm evoked from all subregions of the mPFC. Injections into the cingulate cortex evoked reductions in central respiratory function exclusively, whereas in ventral sites, particularly the infralimbic region, increases in respiratory drive and frequency, and metabolic and cardiac outflows were evoked. Disinhibition of sites in surrounding regions revealed that the LSN could evoke cardiovascular changes accompanied by distinct oscillations in SNA, as well as increases in respiratory amplitude. We show that activation of neurons within the mPFC and LSN influence respiratory, metabolic and cardiac outflows in a site‐dependent manner. This study has implications with respect to the altered PFC neuronal activity seen in stress‐related and mental health disorders, and suggests how basic physiological systems may be affected.