Abstract Objectives To evaluate the mechanism of action of the effect of digested total proteins (DTP), albumin, and glutelin from chia seed to prevent and inhibit inflammation in 3T3-L1 adipocytes. Methods Preadipocytes (3T3-L1) were differentiated into mature adipocytes and received DTP, digested albumin, or glutelin (1 mg/ml) from chia seed together with conditioned medium (CM) from inflamed macrophages during 48 h (prevention), or the digested samples were added after 48 h of CM-stimulated inflammation (inhibition). ROS and cytokines secretion (IL-10, IL-12, IL-6, MCP-1, PGE2, and TNF-α) were analyzed by ELISA and lipid accumulation by oil red-O staining, triglyceride content, lipase activity and expression of proteins (PPAR-γ, SREBP1, FAS, LPL, COX-2, iNOS, and NF-κB) by western-blot. The interactions of peptides with FAS, MAGL, and PPAR-γ were evaluated in silico. Data analyses were performed in triplicate from two independent experiments by ANOVA and post-hoc of Tukey (P < 0.05). Results DTP and digested albumin and glutelin in both, prevention and inhibition of induced inflammation, decreased the expression of PPAR-γ more than 50% (P < 0.05). Digested samples reduced TNF-α secretion, ROS production, lipid accumulation, iNOS and COX-2 expression, especially glutelin (−71, −53, −15, −75, and -85%, respectively) on prevention of inflammation. Albumin digest inhibited NO and PGE2 (−42 and 64%, respectively). DTP reduced the lipase activity (−13%), triglyceride content (−27%), and NF-κB expression (−48%) (P < 0.05). On inhibition of inflammation, only SREBP-1 expression was reduced more than 33% (P < 0.05) by every digested protein. DTP was effective to reduce LPL (-32%), FAS (−29%), iNOS (−52%), and COX-2 (−66%) expression, as well as NO secretion (−15%), and triglyceride content (−18%) (P < 0.05). Peptides TGPSPTAGPPAPGGGTH and YLGAHPGTAN, from digested albumin, showed the highest interaction with PPAR-γ (−9.1 kcal/mol) and MAGL (−7.8 kcal/mol), respectively. Peptide APSPPVLGPP from DTP, showed the highest interaction with FAS (−9.8 kcal/mol). Conclusions Digested samples from chia seed were effective in preventing and even inhibiting inflammation in adipocytes by inhibition of PPAR-γ and NF-κB pathways which highlight the effectiveness these digested proteins against obesity complications. Funding Sources CNPq and CAPES (Brazil), and NIFA HATCH (USA).