Introduction: Resilience to anticancer treatment for colorectal cancer (CRC) among older patients varies. Many experience weight loss, physical decline, falls, and hospitalization during treatment, often leading to early discontinuation of otherwise effective chemotherapy. Screening for vulnerability might help to identify patients at risk of these adverse outcomes in older adults. Materials and Methods: This is a secondary analysis from the GERICO trial. Patients aged ≥70 years assessed for chemotherapy for CRC were screened for eligibility for the GERICO trial with the geriatric-8 (G8) frailty screening tool. The present study population comprised patients who were (1) screened with G8 but for reasons not included in the GERICO study and (2) patients who were randomized to the GERICO control group. We evaluated whether patients identified as vulnerable with G8 (≤14/17) or retrospectively constructed mG8 (≥6/35) had higher risk of experiencing decline in performance status (PS), falls, and unplanned hospitalization during treatment. The association between frailty status and the adverse outcomes was analyzed with univariate and multivariate logistic regression. The discriminative ability of G8/mG8 to predict outcomes was analyzed using the area under the curve for receiver operating characteristics curves. Results: In total, 238 patients (median age 74 years [range 70–91]) were included in this analysis. More vulnerable than fit patients experienced decline in PS (G8: 41% vs. 14%, p = 0.006 and mG8: 28% vs. 17%, p = 0.04) during treatment. Furthermore, more vulnerable than fit patients experienced falls (G8 14% vs. 6% p = 0.04) and unplanned hospitalization (G8: 31% vs. 14%, p = 0.009 and mG8: 34% vs. 13%, p < 0.001). Multivariate analyses showed an association between G8 vulnerability and decline in PS, falls, and hospitalization. Discussion: Patients with G8 or mG8 vulnerability were more likely to experience decline in PS and unplanned hospitalization during chemotherapy for CRC than fit patients. More G8 vulnerable patients experienced falls compared with fit patients. Appropriate interventions should be offered to older patients with CRC assessed as vulnerable with G8 or mG8 to maintain PS during chemotherapy.