Partially defatted baru nut cake (BNC), a baru processing by-product, is a remarkable source of phenolic compounds. However, little is known about the bioaccessibility of its phenolic compounds and antioxidant capacity after gastrointestinal digestion, as well as the cytotoxicity and anti-inflammatory potential of the digested fraction. This study aimed to evaluate the antioxidant capacity and bioaccessibility of phenolic compounds in BNC after in vitro simulation of gastrointestinal digestion. The effect of the bioaccessible fraction on the cytotoxicity and the inflammatory response of LPS/IFN-γ-stimulated macrophages (J774A.1 cell line) were also assessed. Undigested BNC had a high content of phenolic compounds (476.98 mg GAE/100 g), particularly catechin, hesperidin, gallic acid, and procyanidin B2. After the in vitro simulated gastrointestinal digestion, the total phenolic content increased to 2746.1 mg GAE/100 g at the intestinal phase. The dialyzed fraction was not deleterious to cell viability and reduced the production of IFN-γ (DF 1:10), IL-6 (DF 1:50), and ROS (DF 1:50 and 1:100) in LPS/IFN-γ-stimulated cells. Non-dialyzed fraction, which may exert potential prebiotic effects, showed high antioxidant capacity, and the main compounds found in this fraction were procyanidin B2 (30.7 mg/100 g), gallic acid (16.6 mg/100 g), quercetin-3-glucoside (8.6 mg/100 g), and procyanidin B1 (8.3 mg/100 g). Our results indicate that the baru by-product may have promising beneficial effects on health, with antioxidant and anti-inflammatory potential, as part of novel foods or as a functional ingredient in food formulations.