Lipases are enzymes that catalyze the hydrolysis of ester bonds of triacylglycerols at the oil–water interface, generating free fatty acids, glycerol, diacylglycerol, and monoacylglycerol, which can be produced from the fermentation of agro-industrial by-products rich in fatty acids, such as cupuaçu fat cake. In this study, Yarrowia lipolytica IMUFRJ50682 was used for lipase production from cupuaçu fat cake in solid-state fermentation (SSF) associated with soybean meal. The 2:1 ratio of cupuaçu fat cake/soybean meal increased the lipase activity of Y. lipolytica via SSF by approximately 30.3-fold compared to that in cupuaçu without supplementation. The optimal conditions for Y. lipolytica to produce lipase were obtained by supplementation with peptone, urea, and soybean oil (all at 1.5% w/v), reaching values of up to 70.6 U g−1. These results demonstrate that cupuaçu fat cake associated with soybean meal can be used for lipase production and adds value to cupuaçu by-products. Furthermore, the proper processing of by-products can contribute to improving the economic viability of the biotechnological processing industry and help prevent the accumulation of waste and environmental pollution.