Research suggests that cancer survivors have an interest in lifestyle changes following a diagnosis. However, few studies have prospectively investigated whether these changes result in positive outcomes. The objective of this study was to examine the associations between fish oil supplementation and quality of life (QoL), cancer recurrence, and all-cause mortality in Stage 2 colorectal cancer (CRC) patients following diagnosis. Four hundred fifty-three patients were enrolled from the North Carolina Cancer Registry from 2009 to 2011. Data on demography, treatment, and health behaviors were collected at diagnosis, 12-, and 24 mo postdiagnosis. Generalized estimating equations were performed to examine fish oil supplementation in relation to QoL, recurrence, and all-cause mortality. An increase in fish oil supplementation over 24 mo postdiagnosis was associated with an increase in the physical component score of the 12-item Medical Outcomes Short Form (β = 2.43, 95% CI: 0.10-4.76). Supplementation showed no association with the Functional Assessment of Cancer-Colorectal, cancer recurrence or mortality across the 24-mo follow-up. This study suggests that fish oil supplementation may improve symptom-related QoL (i.e., physical functioning) in Stage 2 CRC patients following diagnosis. Future research should address the dose-dependent effects of this relationship.