Background: Patients who receive radiotherapy (RT) for breast cancer often report pain and fatigue which contribute negatively to quality of life (QoL). We aim to identify demographic, treatment, and disease characteristics associated with pain and fatigue using the Edmonton Symptom Assessment Scale (ESAS). Methods: We identified all patients diagnosed with non-metastatic breast cancer from 2011 Jan-2017 Jun at the Odette Cancer Centre with at least one ESAS completed pre- and post-RT. Data on systemic treatment, RT, demographics, and disease stage were extracted. To identify factors associated with pain and fatigue pre- and post-RT and their changes, univariate and multivariable linear regression analysis was conducted. p < 0.05 was considered statistically significant. Results: This study included 1222 female patients (mean age 59 years old) who completed ESAS on average 28- and 142-days pre-RT (baseline) and post-RT respectively. In multivariable analysis, higher baseline pain scores associated with adjuvant chemotherapy (p < 0.001) and eventual receipt of locoregional (p = 0.026) or chest wall RT (p = 0.003), whereas higher baseline fatigue scores associated with higher disease stages (p = 0.001) and locoregional RT (p < 0.001). Post-RT symptom severity correlated only with locoregional RT (higher pain scores, p < 0.001). Reductions in pain was associated with adjuvant chemotherapy (p = 0.002) and chest wall RT (p = 0.031). Reduction in fatigue was associated with adjuvant chemotherapy (p = 0.011) and locoregional RT (p = 0.007) although both had higher pre-RT scores in univariate analysis. Conclusions: Patients at higher disease stages or who received chemotherapy or chest wall RT tended to experience more severe short-term morbidity. However, patients who received locoregional RT tended to have greater pain that persisted after RT completion compared to those who did not.