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Purpose: Although there are many studies that have examined substance use and mental health concerns in rural areas, there is a paucity of research related to the prevalence of substance use and mental well‐being in agriculturally based occupations. This study aimed to determine the prevalence of alcohol and opioid misuse and anxiety among adults in agriculturally based occupations in the rural Midwest and to determine the risk factors for alcohol misuse. Methods: Data were collected via mailed surveys with 1,791 surveys returned. Participants completed the Alcohol Use Disorder Identification Test, the Drug Abuse Screening Test‐1, the Generalized Anxiety Disorder Screener, and reported demographic data. Multivariable logistic regression was used to examine factors associated with alcohol misuse. Results: Younger age, male, not married, agriculturally based workers were significantly associated with alcohol misuse. For opioid use, the highest prevalence rate (10%) was found among direct agricultural workers who were not married and in the age group 19‐39. The highest anxiety prevalence rate was found in participants aged 19‐39 (15.5%) who also scored in the highest level of alcohol misuse with a prevalence rate of 27.9%. Conclusions: Future research is suggested in the areas of gender identity and anxiety in agricultural populations and agriculturally based occupations as protective factors for opioid misuse. [ABSTRACT FROM AUTHOR]