Background/Objectives: Sarcopenia predicts increased morbidity and mortality in gastrointestinal (GI) cancer. This study evaluated the longitudinal association between changes in the skeletal muscle index (SMI) and serum procollagen type III N-terminal peptide (PIIINP), together with sarcopenia and malnutrition screening tools (SARC-F, SARC-CalF, MUST), during chemotherapy for GI cancer. Methods: In this prospective single-center study, 170 patients with GI cancer were assessed at baseline and month 6; 48 died, and longitudinal analyses included the 122 survivors. SMI was derived from bioelectrical impedance analysis (Tanita SC-330) using the Janssen equation, and serum PIIINP was measured at both time points. The primary endpoint was the association between the percentage changes in SMI and PIIINP. Results: BMI, SMI, and handgrip strength decreased and SARC-F and SARC-CalF scores increased significantly (all p < 0.001); the prevalence of low muscle mass rose from 29% to 52%, and PIIINP increased significantly. The percentage changes in SMI and PIIINP were strongly inversely correlated (ρ = −0.733, p < 0.001). In the parsimonious multivariable model, the percentage change in PIIINP (β = −0.47) and month-6 albumin (β = 0.31) were independently associated with the change in SMI (R² = 0.37); the albumin association was model-dependent and not retained in the expanded model. Conclusions: In patients with GI cancer receiving chemotherapy, progressive muscle loss over six months was accompanied by a rise in the circulating collagen turnover marker PIIINP. Because the study was observational, restricted to survivors, and based on a non-muscle-specific marker, causal and muscle-specific inferences are unwarranted; PIIINP nonetheless merits further evaluation as a monitoring biomarker.