Objective <p>This study examines the relationship between opioid use disorder (OUD) and healthcare use, especially regarding length of stay, total charges, and costs in U.S. hospitals from 2005 to 2020.</p> Methods <p>We used the Healthcare Cost &amp; Utilization Projects (HCUP) National Inpatient Sample (NIS) data to compare these outcomes between patients with and without OUD. We applied generalized linear modeling (GLM) with gamma distribution and log link to assess the effect of OUD on the three outcomes.</p> Results <p>Our results show that hospital stays for patients with OUD were significantly longer, while total charges and costs were lower than those without OUD. Over time, there was a tendency towards convergence between total charges and costs for OUD and non-OUD patients. The study also revealed that the severity of illness was strongly related to length of stay, total charge, and total cost, and OUD patients with greater illness severity and comorbid conditions demonstrated increased outcomes compared to those without OUD, with increased total costs and charges in 2020.</p> Conclusions <p>Our results offer important insights into the healthcare impact of OUD. Future studies should use patient-level data to better understand the overall healthcare use per person rather than per hospital stay, as well as more recent years of data to study greater Covid-19 specific impacts.</p> Implications <p>The study emphasizes the need for more efforts to decrease the prevalence of OUD in the U.S. to help ease the pressure on the healthcare system. It also demonstrates the potential influence of the severity of illness and comorbidity on healthcare use, suggesting a need for specific interventions for patients with severe conditions.</p>