In the presented investigations we performed a quantitative proteomic analysis of rat liver and kidney tissues following exposure to morphine (10 mg/kg, once daily, for 10 days, intraperitoneally), compared to untreated controls. Although opioids are generally considered safe for both organs during short-term pain therapy, our data revealed significant alterations in protein expression that extend beyond classical metabolic enzymes. Notable, differences were observed in proteins related to pro- and anti-apoptotic signaling, oxidative stress response, transport mechanisms, transmembrane receptors, nucleic acid metabolism, and regulators of alternative splicing, among others. Liver tissue exhibited primarily adaptive changes, including upregulation of metabolic enzymes and subtle indications of oxidative stress based on marker profiles. In contrast, the kidneys displayed a broader spectrum of proteomic alterations, affecting a wider array of functional pathways, suggesting that this organ may be more susceptible to morphine-induced toxicity or that of its metabolites. Here DDA data from both experiments, on liver and kidneys, are presented.