Key points Hypoxia activates peripheral chemoreceptors producing an increase in breathing and arterial pressure. In conditions of sustained hypoxia, an increase in ventilation and arterial blood pressure is observed that persists after the return to normoxia. We show in rats that sustained hypoxia for 24 h produces glutamate‐dependent changes in the activity of expiratory and sympathetic neurones of the rostral ventrolateral medulla, which are essential for the control of respiratory and sympathetic activities. These neuronal changes induced by sustained hypoxia are critical for the emergence of coupled active expiration and augmented sympathetic activity. These findings contribute to a better understanding of cardiorespiratory adjustments associated with sustained hypoxia in individuals experiencing high altitudes. Abstract Individuals experiencing sustained hypoxia (SH) exhibit adjustments in the respiratory and autonomic functions by neural mechanisms not yet elucidated. In the present study we evaluated the central mechanisms underpinning the SH‐induced changes in the respiratory pattern and their impact on the sympathetic outflow. Using a decerebrated arterially perfused in situ preparation, we verified that juvenile rats exposed to SH (10% O2) for 24 h presented an active expiratory pattern, with increased abdominal, hypoglossal and vagal activities during late‐expiration (late‐E). SH also enhanced the activity of augmenting‐expiratory neurones and depressed the activity of post‐inspiratory neurones of the Bötzinger complex (BötC) by mechanisms not related to changes in their intrinsic electrophysiological properties. SH rats exhibited high thoracic sympathetic activity and arterial pressure levels associated with an augmented firing frequency of pre‐sympathetic neurones of the rostral ventrolateral medulla (RVLM) during the late‐E phase. The antagonism of ionotropic glutamatergic receptors in the BötC/RVLM abolished the late‐E bursts in expiratory and sympathetic outputs of SH rats, indicating that glutamatergic inputs to the BötC/RVLM are essential for the changes in the expiratory and sympathetic coupling observed in SH rats. We also observed that the usually silent late‐E neurones of the retrotrapezoid nucleus/parafacial respiratory group became active in SH rats, suggesting that this neuronal population may provide the excitatory drive essential to the emergence of active expiration and sympathetic overactivity. We conclude that short‐term SH induces the activation of medullary expiratory neurones, which affects the pattern of expiratory motor activity and its coupling with sympathetic activity.