To investigate the association of low-grade radiation injury (LGRI) and high-grade radiation injury (HGRI) following prostate cancer treatment with mental health diagnoses and therapy. A retrospective study of men diagnosed with prostate cancer who were treated with radiotherapy. Men were followed to assess for LGRI or HGRI using IBM MarketScan. Cohorts included: no injury (no-RI), LGRI, HGRI, and controls. Mental health diagnoses and related treatment (medication/therapy) were identified using ICD-10 codes, CPT codes, and national drug codes. A multivariable Cox proportional hazards model from time of radiation to first instance of mental health diagnosis was modeled against injury group, age, and comorbidities. Between 2011-2020 we identified 55,425 men who received radiotherapy for prostate cancer. 22,879 (41.3%) experienced a LGRI while 4,128 (7.4%) experienced a HGRI. Prior to radiation therapy, mental health diagnoses were equally distributed across cohorts (p>0.05). Every marker of mental health showed a step-wise increase in incidence from no-RI to LGRI to HGRI except for alcohol abuse. Use of mental health medications and therapy visits were slightly more likely in the LGRI and HGRI groups prior to radiation, however this difference was greatly increased post-radiation therapy. LGRI (HR 1.38; p<0.001) and HGRI (HR 2.1;p<0.001) were independently associated with an increased likelihood of mental health diagnoses. LGRI and HGRI following prostate cancer radiotherapy are associated with increased risk of mental health diagnosis, medication use, and therapy need compared to men who do not develop injuries. The most common mental health diagnoses were depression and anxiety.