Background: The FACT-G contains 27 questions within 4 subscale domains [Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, Functional Well-Being] related to health-related quality of life (QOL) in the past 7 days, with higher scoring indicating better QOL. In this prospective cohort study, we assessed longitudinal FACT-G data with treatment response and survival outcomes among patients with metastatic GI cancer. Methods: From 5/2019-11/2021, we enrolled patients at Massachusetts General Hospital with metastatic GI cancer to study before their treatment start. We collected the FACT-G survey at baseline (start of treatment) and 1-month later. We then used regression models to assess associations of 1-month changes in FACT-G with treatment response and survival outcomes (progression-free survival [PFS] and overall survival [OS]). For treatment response, clinical benefit was defined as decreased or stable tumor burden versus progressive disease at the time of first scan. All models were adjusted for baseline values of each respective variable. Results: We enrolled 203 of 262 patients approached (77.5% enrollment); 160 had 1-month follow-up data (median age = 63.0 years [range: 28.0-84.0 years], 66.3% male, 45.6% pancreaticobiliary cancer). For treatment response, 66.3% experienced a clinical benefit and 33.8% had progressive disease at the time of first scan (mean time to first scan = 2.7 months). Increases in FACT-G Total were predictors for treatment response (OR = 1.05, p = 0.0028), and improved PFS (HR = 0.98, p = 0.026) and OS (HR = 0.98, p = 0.038). Increases in FACT-G Emotional were associated with clinical benefit at the time of first scan (OR = 1.18, p = 0.0024), improved PFS (HR = 0.94, p = 0.023), and improved OS (HR = 0.93, p = 0.012). Improvement in FACT-G Physical were predictors for clinical benefit at time of first scan (OR = 1.08, p = 0.038) and better PFS (HR = 0.96, p = 0.038), while increases in FACT-G Functional were associated with improved PFS (HR = 0.96, p = 0.034) and OS (HR = 0.96, p = 0.019). Finally, changes in FACT-G Social were only associated with treatment response (OR = 1.16, p = 0.011). Conclusions: We found that 1-month increases in FACT-G can predict for treatment response and improved survival outcomes in patients with metastatic GI cancers. Notably, the FACT-G Total and FACT-G Emotional subscore predicted for all three outcomes of interest, while the FACT-G Social only predicted for clinical benefit at first scan. These data support previous findings indicating the possible use of early changes in patient-reported outcomes as a biomarker for early treatment response while emphasizing the growing need to integrate more patient-centric interventions into clinical care for cancer patients. Clinical trial information: NCT04776837.