Simple Summary: Pancreatic adenocarcinoma is an aggressive tumour with a high mortality, often diagnosed at advanced stages. The current standard of care for first-line therapy is multi-agent FOLFIRINOX or gemcitabine plus nab-Paclitaxel. Pancreatic adenocarcinoma predominantly effects the elderly population, albeit these patients are underrepresented in clinical trials. This systematic review aims to review the efficacy of multi-agent versus single-agent chemotherapy for advanced pancreatic adenocarcinoma in elderly versus young populations. Purpose: To systematically review all studies comparing multi-agent to single-agent chemotherapy in the first and second-line setting for unresectable pancreatic adenocarcinoma, so as to compare the outcomes of young and elderly patients. Methods: This review searched three databases for relevant studies. The inclusion criteria were diagnosis of locally advanced or metastatic pancreatic adenocarcinoma, comparison of an elderly versus young population, comparison of single-agent versus multi-agent chemotherapy, data on survival outcomes, and randomised controlled trials. The exclusion criteria were phase I trials, incomplete studies, retrospective analyses, systematic reviews, and case reports. A meta-analysis was performed on second-line chemotherapy in elderly patients. Results: Six articles were included in this systematic review. Three of these studies explored first-line treatment and three explored second-line treatment. In the subgroup analysis, the meta-analysis showed statistically improved overall survival for elderly patients receiving single-agent second-line treatment. Conclusions: This systematic review confirmed that combination chemotherapy improved survival in the first-line treatment of advanced pancreatic adenocarcinoma, regardless of age. The benefit of combination chemotherapy in second-line studies for elderly patients with advanced pancreas cancer was less clear. [ABSTRACT FROM AUTHOR]