We examined the association of self-reported substance use with quality of life (QOL), and pain severity and interference among Veterans who are survivors of head and neck cancer (HNC). We administered a cross-sectional survey to Veterans with chronic pain who were at least 2 years post-HNC diagnosis. We examined associations between self-reported nicotine, alcohol, and cannabis use with measures of HNC related QOL, pain interference, pain severity, and pain management self-efficacy. We hypothesized current substance use would be positively associated with pain interference and severity and inversely associated with QOL. The final sample included 191 Veterans, the majority were aged 66 years or older (58.7%), male (97.4%) and White identifying (82.7%). One-third of participants endorsed moderate (29.8%) or high (4.7%) current nicotine use, and one-quarter had moderate (21.5%) or high (2.7%) alcohol use. Compared to those who did not endorse alcohol use, high alcohol use was significantly associated with a 25-point lower score on eating quality of life (on a 0-100 scale) ( = 0.03). In interaction models, no/low nicotine use and low self-efficacy had significantly higher pain interference compared to those with high self-efficacy (5.8 (95% CI: 5.1, 6.6); 2.4 (95% CI: 1.6, 3.2). Among HNC survivors, current alcohol and nicotine use is associated with lower quality of life and higher pain interference. Pain and substance use psychosocial services with focus on chronic pain, alcohol, and nicotine use, may improve QOL for patients post-HNC treatment.