Purpose <p>The systemic influence of obstructive sleep apnea(OSA), particularly in those with severe OSA (sOSA), has frequently been disregarded. An investigation was conducted to examine the variations of reactive oxygen species (ROS) and metabolomic drifts, as well as their interrelations, in adult OSA patients.</p> Methods <p>A total of 22 male patients were enrolled after undergoing polysomnography (PSG), and blood samples were obtained. Following the measurement of ROS levels in polymorphonuclear neutrophils (PMNs), plasma samples were combined and analyzed using both Gas Chromatography-Mass Spectrometry (GC–MS) and Liquid Chromatography-Mass Spectrometry (LC–MS).</p> Results <p>Patients with sOSA had a higher body mass index (BMI) (p = 0.005) and more negative PSG measures compared to those with mild/moderate OSA (mOSA). Although there was no remarkable difference in neutrophil ROS between the mOSA and sOSA group, further analysis indicated sleep fragmentation was associated with ROS production(p = 0.043 for N3%, p &lt; 0.01 for Arousal Index). Integrated metabolomics analysis revealed significant alterations in 59 metabolites from GC–MS and 27 metabolites from LC–MS in sOSA patients. These substantial changes perturbed various pathways, including the FoxO signaling pathway and its upstream PI3K-Akt signaling pathway, and so on. Notably, the retrograde endocannabinoid signaling pathway was the sole common pathway identified in both GC–MS and LC–MS data.</p> Conclusions <p>This study sheds light on the systemic impact of OSA, particularly in severe cases, by uncovering extensive disturbance of metabolic pathways. The identification of retrograde endocannabinoid signaling shifts in severe OSA adults highlights its potential impact in the sleep disorder and its broader repercussions in the body.</p>