Simple SummaryCollagen type XI alpha 1 (COL11A1) is a novel biomarker associated with poor survival in ovarian cancer and a promoter of ovarian cancer cell resistance to cisplatin. However, it is poorly understood how COL11A1 promotes ovarian cancer cisplatin resistance. We performed assays to discover the biological molecules that are activated by COL11A1 in ovarian cancer cells. We found that heat shock protein 27 (HSP27), a cellular stress response protein, is activated by COL11A1. Furthermore, we observed that depletion and drug inhibition of HSP27 makes ovarian cancer cells grown on COL11A1 to be more susceptible to cisplatin treatment. We also discovered that ovarian cancer cells upregulate fatty acid oxidation (FAO), a metabolic process that breaks down fats to generate energy and biomolecules, to compensate for the loss of HSP27. Our findings have therapeutic implications for clinicians who wish to treat ovarian tumors that maintain high levels of COL11A1 and HSP27.Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. We have previously reported that COL11A1 activates Src-Akt signaling through the collagen receptors discoidin domain receptor 2 (DDR2) and integrin α1β1 to confer cisplatin resistance to ovarian cancer cells. To identify the potential signaling molecules downstream of COL11A1 signaling, we performed protein kinase arrays and identified heat shock protein 27 (HSP27) as a potential mediator of COL11A1-induced cisplatin resistance. Through receptor knockdown and inhibitor experiments, we demonstrated that COL11A1 significantly upregulates HSP27 phosphorylation and expression via DDR2/integrin α1β1 and Src/Akt signaling in ovarian cancer cells. Furthermore, genetic knockdown and pharmacological inhibition of HSP27, via ivermectin treatment, significantly sensitizes ovarian cancer cells cultured on COL11A1 to cisplatin treatment. HSP27 knockdown or inhibition also decreases NFκB activity as well as the expression of inhibitors of apoptosis proteins (IAPs), which are known downstream effector molecules of COL11A1 that promote cisplatin resistance. Interestingly, HSP27 knockdown or inhibition stimulates ovarian cancer cells to upregulate fatty acid oxidation (FAO) for survival and cisplatin resistance, and dual inhibition of HSP27 and FAO synergistically kills ovarian cancer cells that are cultured on COL11A1. Collectively, this study identifies HSP27 as a novel and druggable COL11A1 downstream effector molecule that may be targeted to overcome cisplatin resistance in recurrent ovarian cancer, which often overexpress COL11A1.