Emerging evidence indicates that metabolic dysregulation drives prostate cancer (PCa) progression and metastasis. AMPK is a master regulator of metabolism although its role in PCa remains unclear. Here we show that genetic and pharmacological activation of AMPK provides a dramatic protective effect on PCa progression in vivo. We show that AMPK activation induces PGC1-alpha expression leading to a catabolic metabolic reprogramming of PCa cells. This catabolic state is characterised by increased mitochondrial gene expression, increased fatty acid oxidation, decreased lipogenic potential, decreased cell proliferation and decreased cell invasiveness. Together, these changes inhibit PCa disease progression. Additionally, we identify a gene network involved in cell cycle regulation that is inhibited by AMPK activation. Strikingly, we show a strong correlation between this gene network and PGC1-alpha gene expression in human PCa. Taken together our findings strongly support the use of AMPK activators for clinical treatment of PCa to improve patient outcome.