Ethylene oxide is extensively used for sterilizing medical equipment, and its carcinogenicity has been well documented. Furthermore, the onset of multiple diseases, including diabetes and hypertension, has been demonstrated to be associated with exposure to this compound. However, its association with osteoarthritis risk remains elusive. The study analyzed data from the National Health and Nutrition Examination Survey from 2013-2020, which included 6088 American adults, among whom 763 (12.5%) were diagnosed with osteoarthritis. We utilized a weighted generalized linear model to assess the correlation between ethylene oxide exposure levels and osteoarthritis risk. This study used mediation analysis to assess the functions of indicators of oxidative stress (γ-glutamyl transferase) and inflammation (alkaline phosphatase, white blood cell count, neutrophil count, and lymphocyte count) as mediators of how ethylene oxide affects osteoarthritis. The analysis revealed that elevated levels of ethylene oxide were correlated with a higher risk of osteoarthritis, even when controlling for other variables. The odds of developing osteoarthritis were 1.86 times higher in the fourth quartile than in the first quartile (95% confidence interval: 1.20-2.88, P = 0.0097, P for trend = 0.0087). Subgroup analyses indicated consistency across different cohorts. Mediation analysis revealed that oxidative stress (γ-glutamyl transferase), not inflammation, was the mediator linking ethylene oxide levels to the risk of osteoarthritis. This finding in a sample of American adults revealed a direct relationship between exposure to ethylene oxide and increased osteoarthritis risk. Oxidative stress has been suggested as a possible biological explanation for osteoarthritis caused by ethylene oxide.