With the rise of drug misuse among workers in recent years, preliminary research on potential risk factors in the workplace of single-type of drug misuse has been reported. This is the first study to examine cross-sectional associations of work stress, in terms of effort-reward imbalance, with multiple drug misuse (including any drug misuse, opioid misuse, sedatives misuse, cannabis misuse, and other drug misuse) during the past 12 months in a national sample of U.S. workers. Data of 2211 workers were derived from the nationally representative and population-based Midlife in the United States (MIDUS) study. Internal consistency reliability and factorial validity of a 17-item effort-reward imbalance measure were robust and satisfactory. After adjustment for relevant covariates, logistic regression analyses showed that workers experiencing effort-reward imbalance at work had significantly higher odds of any drug misuse (OR and 95% CI = 1.18 (1.03, 1.37)), especially opioid misuse (OR and 95% CI = 1.35 (1.07, 1.69)) and other drug misuse (OR and 95% CI = 1.36 (1.01, 1.83)). The findings suggest that a stressful work environment may act as a determinant of drug misuse, and further prospective evidence is needed.