Patients with multiple brain metastases may be treated with whole-brain radiation therapy (WBRT). For these patients, symptom palliation and improvement of quality of life (QOL) and performance status is of the upmost importance. The objective of the present study was to determine the symptom experience and overall QOL in patients with brain metastases before and after WBRT. A total of 14 symptom scores and overall QOL were collected prospectively in 217 patients for up to 3 months. Wilcoxon signed rank test was applied to determine significant symptoms and QOL changes. Spearman's correlations were applied to determine the relationship between symptom scores and QOL. Appetite loss, weakness, and nausea significantly increased from baseline, while balance, headache, and anxiety significantly decreased from baseline. At baseline, all symptoms other than coordination were significantly correlated with QOL. At 1-month follow-up (FU), changes in concentration, weakness, coordination, and balance were significantly associated with QOL changes. At 2-month FU, changes in pain, insomnia, concentration, balance, and depression were significantly associated with QOL changes. At 3-month FU, only change in nausea was significantly associated with QOL changes. Following WBRT, certain symptoms may influence overall QOL to a greater extent than others, which may fluctuate with time.