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Background/Objectives: Malnutrition is highly prevalent in patients with advanced colorectal cancer (CRC) and is associated with poorer treatment tolerance, reduced quality of life, and worse clinical outcomes. Chemotherapy regimens incorporating irinotecan are commonly used in later treatment lines but present a distinct toxicity profile characterized mainly by gastrointestinal symptoms and functional decline, which may negatively affect nutritional status. This study aimed to evaluate the impact of irinotecan-containing chemotherapy regimens on nutritional status and functional capacity in patients with advanced CRC using the Patient-Generated Subjective Global Assessment (PG-SGA). Methods: A cross-sectional observational study was conducted in 91 adult patients with histologically confirmed stage III–IV colorectal adenocarcinoma undergoing active systemic chemotherapy between November 2023 and June 2024. Demographic and clinical variables, treatment regimens, and exposure to irinotecan were recorded. Nutritional status was assessed using the PG-SGA, and body composition was evaluated by multifrequency bioelectrical impedance analysis. Associations between irinotecan exposure and nutritional, functional, and symptom-related variables were analyzed using χ2 or Fisher’s exact tests. Results: Thirteen patients (14.3%) received irinotecan-containing regimens, most frequently combined with FOLFOX. Patients exposed to irinotecan presented higher PG-SGA scores, indicating a greater nutritional burden. Although most gastrointestinal symptoms did not reach statistical significance, early satiety (p = 0.041) and functional deterioration (p = 0.039) were significantly associated with irinotecan administration, while nausea (p = 0.089) and vomiting (p = 0.087) showed trends toward significance. The subgroup treated with FOLFOX–irinotecan also demonstrated a higher frequency of functional impairment compared with those receiving FOLFOX alone. Conclusions: Irinotecan-containing chemotherapy regimens in advanced CRC may be associated with a distinct pattern of nutritional deterioration primarily driven by functional decline and gastrointestinal symptoms affecting food intake. Systematic nutritional assessment using validated tools such as the PG-SGA may allow early identification of vulnerable patients and support the implementation of timely multimodal interventions aimed at improving treatment tolerance and clinical outcomes.