Docetaxel is a first line chemotherapy agent, which stabilizes microtubules in metastatic prostate cancer (PCa). Resistance to Docetaxel and its side effects remain as obstacle for its efficacy in monotherapy. Recently, combination with novel adjuvants have been emerged as a beneficial alternative strategy, which targets multiple important pathways and also requires lower therapeutic dosage, proposing as a strategy to overcome drug resistance. This study investigated whether Liraglutide, a Glucagon Like Peptide-1 Receptor agonist, can reinforce the effect of Docetaxel on LNCaP prostate cancer cell line. Cells were treated by Liraglutide and Docetaxel, alone and in combination. Cytotoxicity was evaluated by MTT assay. Compusyn and Combenefit softwares were used in order to evaluate synergistic efficacy. Apoptosis was determined by Cell cycle analysis and Annexin-V/Propidium iodide staining through flow cytometry. However, the mRNA level of pro-apoptotic gene “Bax” and anti-apoptotic “Bcl-2” were evaluated by quantitative Real-Time PCR. Also, phosphorylation level of ERK1/2 and AKT proteins was investigated by western blotting technique. The results showed that Docetaxel and Liraglutide decreased the viability of LNCaP cells synergistically, caused cell cycle arrest and induced apoptosis potentially. The key proteins’ evaluation in ERK/MAPK and AKT/PI3K pathways revealed a significant reduction in phosphorylation level of cells exposed to combination of drugs. Our results suggest that, the combination of Liraglutide and Docetaxel could be considered as a potent strategy in enhancing the efficacy of treatment, decreasing the Docetaxel therapeutic dose and thereby lowering systemic toxicities and resistances.Copyright © 2020. Published by Elsevier B.V.