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Objective: Current studies have indicated that diabetes mellitus (DM) is highly prevalent in patients with cancer, but there is little research on consequences on the well‐being of patients during cancer treatment. This analysis evaluates the relationship between DM and patient‐reported outcomes (PRO) in patients with cancer, using a large and well‐characterized cohort. Methods: This study utilized the Total Cancer Care protocol at the University of Utah Huntsman Cancer Institute. For this analysis, we integrated data from electronic health records, the Huntsman Cancer Registry, and routinely collected PRO questionnaires. We assessed the association between DM in patients with cancer and PRO scores for anxiety, depression, fatigue, pain interference, and physical function using multiple linear regression and t‐tests. Results: The final cohort comprised 3512 patients with cancer, with a mean age of 57.8 years at cancer diagnosis. Of all patients, 49.1% (n = 1724) were female, with 82.0% (n = 2879) patients reporting PROs at least at one time point. Compared with patients who responded, nonresponders were more often female (p = 0.0035), less frequently non‐Hispanic White (p = 0.0058), and had a higher BMI (p = 0.0759). Patients with cancer and diabetes had worse PRO scores for anxiety (p = 0.0003), depression (p < 0.0001), fatigue (p < 0.0001), pain interference (p < 0.0001), and physical function (p < 0.0001) compared to patients with cancer without diabetes. Significant associations between diabetes and PRO scores were observed for anxiety (β ± SE: 1.27 ± 0.48; p = 0.0076), depression (β ± SE: 1.46 ± 0.45; p = 0.0011), fatigue (β ± SE: 2.11 ± 0.52; p < 0.0001), pain interference (β ± SE: 1.42 ± 0.50; p = 0.0046), and physical function (β ± SE: −2.74 ± 0.48; p < 0.0001). Conclusions: The results of this study suggest that patients with cancer and diabetes may be at greater risk for anxiety, depression, fatigue, higher pain interference, and reduced physical function. Strengthening diabetes management is imperative to address the negative impact of diabetes on PROs. In particular, this may be true for patients with skin, breast, prostate, and kidney cancer. [ABSTRACT FROM AUTHOR]