Prostate tumours are highly dependent on lipids for growth and survival. The androgen receptor (AR) is a major mediator of dysregulated lipid metabolism in prostate cancer, although the molecular mechanisms underlying this phenomenon remain to be fully elucidated. Here, we identified Acyl-CoA Synthetase Medium Chain Family Members 1 and 3 (ACSM1 and ACSM3), enzymes that play a critical role in fatty acid activation, as factors that are directly regulated by AR in prostate cancer. ACSM1 and ACSM3 are highly upregulated in prostate tumours compared to non-malignant tissues and discriminate this cancer type in pan-cancer analyses. Knockdown of ACSM1/3 in PCa cells resulted in growth inhibition (in vitro and in vivo) and depletion of ATP, consistent with both factors having a major role in energy production via fatty acid oxidation. Mass spectrometry-based lipidomics and metabolomics revealed that loss of ACSM1/3 caused prostate cancer cells to accumulate poly-unsaturated fatty acids and switch to a glycolytic phenotype. These phenotypic changes led to mitochondrial oxidative stress and subsequent lipid peroxidation, eventually resulting in cell death. Build-up of mitochondrial reactive oxygen species was abrogated by an iron chelator, ferrostatin-1, suggesting that cell death was due to an iron-dependent form of apoptosis termed ferroptosis. Supporting this concept, over-expression of ACSM1 and ACSM3 elicited resistance to the ferroptosis inducers Erastin and ML210. Collectively, these studies uncover a novel link between AR and lipid metabolism in prostate cancer cells. Importantly, the critical role of ACSM1 and ACSM3 as key regulators of growth and protectors against ferroptosis emphasises their potential as novel therapeutic targets.