Background: Pancreatic adenocarcinoma is one of the deadliest cancers, ranking fourth in mortality and accounting for up to 7% of all cancer related deaths in the United States. For many years, Gemcitabine and its combinations have been the standard first-line treatments for patients with unresectable locally advanced or metastatic pancreatic cancer (aPC). Recently, FOLFIRINOX was shown to be associated with a survival advantage as well. These chemotherapy combinations have not been compared to each other. We conducted this network meta-analysis to evaluate the relative efficacy of the commonly used chemotherapy regimens in patients with aPC. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of aPC; treatment with Gemcitabine (GEM) combined with Capecitabine (CAPE), Erlotinib (ERLO), or nab-Paclitaxel (NABPAC) and treatments with FOLFIRINOX; and randomized studies reporting survival and response rates. A frequentists network meta-analysis was conducted using netmeta package and random-effects model. Results: Six studies comprising a total of 2,717 participants were included. FOLFIRINOX demonstrated a significantly better relative risk (RR) of progression and death (P&D) followed by GEM+NABPAC, GEM+ERLO, GEM+CAPE, and GEM in a decreasing order. When compared to GEM-based combination as a group, FOLFIRINOX maintained its superior RR for P&D. Moreover, FOLFIRINOX and GEM+NABPAC had significantly better response rates than GEM+CAPE and GEM+ERLO. Inconsistency analysis did not reveal any significant differences between direct and indirect estimates. Conclusions: This network meta-analysis is the first to compare and rank commonly used treatment regimens in aPC. It indicates that FOLFIRINOX combination seems to be superior to GEM-based combinations with respect to P&D as well as response rates. Nevertheless, among GEM-based combinations, GEM+NABPAC seems to have the best profile given its lower RR for P&D and higher response rates.