Sarcopenia is associated with poor outcomes in patients undergoing surgery for pancreatic ductal adenocarcinoma (PDAC). However, few studies have assessed changes in sarcopenia during multimodality therapy or its effect on overall survival (OS). Computed tomography (CT) total psoas area index (TPAI) and weighted average Hounsfield units (HU) were measured at each treatment interval in patients with resectable PDAC. Four cohorts were compared: 1. Neoadjuvant chemotherapy plus surgery plus adjuvant chemotherapy (“NSA”; n = 20); 2. surgery plus adjuvant chemotherapy (“SA”; n = 20); 3. neoadjuvant chemotherapy with intent to perform surgery (“Chemotherapy”; n = 24); and 4. treated with palliative intent (“Palliative”; n = 21). Fifty-nine deaths were identified. Median OS was 15.7 months (95% Confidence Interval (CI) 12.7–20.2). Patients who underwent surgery had a higher OS (p < 0.001), with the SA group having a longer OS than the NSA group. Cox regression models identified baseline TPAI (Hazard Ratio (HR) = 0.82; p = 0.04), but not psoas HU, as a significant predictor of OS. The mean decrease in TPAI following neoadjuvant chemotherapy was 0.6 cm2/m2 (p < 0.001; 95% CI −0.8–−0.3) and the mean decrease in HU was 2.7 (p = 0.04, 95% CI −5.4–−0.1). For patients who underwent surgery (NSA and SA cohorts), a decrease in TPAI was associated with worse OS (HR 0.52; p = 0.05). In contrast, decreased HU was associated with worse OS in patients who did not undergo surgery (HR 0.93; p = 0.01). In patients who received neoadjuvant chemotherapy, there was a significant decrease in TPAI and HU during treatment. Prospective studies are warranted to assess the impact of TPAI loss and HU changes on clinical outcomes to better individualize treatment pathways based on a patient's fitness.