Quinoa (Chenopodium quinoa Willd.) is considered an exceptional source of high‐quality protein and may be a good precursor of bioactive components with immunomodulatory effects. Quinoa protein‐enriched fraction (QPF) was isolated from quinoa seeds via alkaline extraction and isoelectric point precipitation and hydrolyzed at the optimum temperature and pH of two food‐grade proteases to produce QPF hydrolysates (QPFH). SDS‐PAGE and LC–MS analyses showed that low‐molecular weight peptides were present in hydrolyzed proteins and that the enzymes effectively hydrolyzed high‐molecular weight proteins evidenced by significantly higher amino acid levels in QPFH. J774A.1 macrophages and mouse bone‐marrow‐derived macrophages (BMDMs) were polarized into an M1‐like (pro‐inflammatory) or M2‐like (anti‐inflammatory) state in the absence or presence of QPF or QPFH. Our results showed that QPFH attenuated M1‐like response as demonstrated by a significantly lowered secretion of pro‐inflammatory cytokines (IL‐6, TNF‐α, IL‐12p40, and IL‐27p28) and nitric oxide (NO) levels. Co‐treatment with QPFH significantly boosted IL‐10 and arginase activity in both M1‐like and M2‐like cells indicating that the samples may promote a phenotypic switch to M2‐like macrophages. Furthermore, QPFH inhibited pro‐inflammatory cytokines in Loxoribine (LOX)‐activated bone marrow‐derived dendritic cells (BMDCs) and inhibited the same cytokines during a 7‐day DC maturation experiment. QPF but not the QPFH influenced the expression of surface antigen molecules in macrophages by decreasing the frequency of MHCI and CD86 expressing cells. Taken together, these findings reveal novel mechanisms that demonstrate the potential of quinoa protein hydrolysates in the development of immunomodulatory functional foods.