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Background: Long-term arsenic exposure is associated with diabetes in adults, the mechanism of which involves insulin resistance. The relationship between arsenic and insulin resistance in adults is unclear. We analyzed the relationship between urinary arsenic and insulin resistance in US adults. Results: We identified 815 adults aged 20–79 years who participated in the 2015–2016 National Health and Nutrition Examination Survey (NHANES). Urinary arsenic, fasting glucose, serum insulin, and other key covariates were obtained from the NHANES data. The association between urinary arsenic and insulin resistance was evaluated by analyzing the urinary arsenic level and homeostasis model assessment-insulin resistance. The median total urinary arsenic level was 6.82 µg/L. After adjusting for possible confounding factors (gender, age, and body mass index), the 80th and 20th percentile odds ratio (OR) was 1.41 (95% confidence interval [CI] 1.07, 1.87); the OR of the 70th and 30th percentiles was 1.41 (95% CI 1.08, 1.84). Conclusions: In most subgroups, after similar adjustment, the relationship between urine total arsenic and insulin resistance remained. Total arsenic exposure in urine may be associated with insulin resistance. Evidence from larger and more adequately powered cohort studies is needed to confirm our results.