Background: Advanced pancreatic adenocarcinoma (PA) remains a formidable challenge with limited therapeutic options. Gemcitabine-based regimens, often combined with novel targeted therapies, are widely employed, yet their comparative efficacy is poorly understood. This network meta-analysis (NMA) aims to systematically evaluate the efficacy of various targeted drug combinations in previously treated patients with advanced or metastatic PA. Methods: We conducted a systematic search of phase III randomized controlled trials (RCTs) published between 2004 and 2024, sourced from PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov. Studies comparing targeted drug combinations with chemotherapy or chemotherapy alone in advanced/metastatic PA were included. Primary outcomes were overall survival (OS) and progression-free survival (PFS), assessed via hazard ratios (HRs) with 95% confidence intervals (CIs) using a Bayesian fixed-effects NMA. Surface under the cumulative ranking (SUCRA) scores were calculated to rank treatment efficacy. Results: Thirteen RCTs, encompassing 5,759 patients and evaluating 13 targeted drug combinations, were included. No statistically significant improvements in OS or PFS were observed for any targeted drug combination compared to gemcitabine monotherapy. Similarly, indirect comparisons among targeted therapies revealed no significant differences. SUCRA rankings identified Gemcitabine plus Sorafenib (Gem-Soraf, 77%) as having the highest probability of ranking first for OS, followed by Gemcitabine plus Rigosertib (Gem-Rigos, 76%), Gemcitabine plus Cetuximab (Gem-Cetux, 62%), and Gemcitabine plus Nimotuzumab (Gem-Nimot, 17%). For PFS, Gem-Soraf (87%) ranked highest, followed by Gem-Cetux (65%), Gemcitabine plus Tipifarnib (Gem-Tipi, 65%), and Gemcitabine plus Erlotinib-Bevacizumab (Gem-Erlot-Beva, 14%). Conclusions: This NMA suggests that Gem-Soraf offers the highest probability of superior OS and PFS among targeted therapies for advanced PA. However, no targeted combination significantly outperformed gemcitabine monotherapy, highlighting the need for further research into personalized treatment strategies.