BACKGROUND: The multifactorial origin of many chronic diseases provides a new framework for the development of multifunctional foods. In this study, the effect of in vitro simulated gastrointestinal digestion of kiwicha (Amaranthus caudatus) proteins on the release of multifunctional peptides was evaluated. RESULTS: Gastric digest showed higher angiotensin I converting enzyme (ACE) inhibitory activity while 60 min gastroduodenal digest showed the highest antioxidant, dipeptidyl peptidase IV (DPP-IV), α-amylase and Caco-2 cell viability inhibitory activities. Peptides >5 kDa were more effective in inhibiting colon cancer cell viability, whereas peptides <5 kDa were mainly responsible for the antioxidant, ACE, DPP-IV and α-amylase inhibitory activities. Thirteen peptides from amaranth sequenced proteins were identified. Structure–activity relationship analysis of the identified sequences pointed to three amaranth fragments, namely FLISCLL, SVFDEELS and DFIILE, as potential peptides able to concurrently exert antioxidant capacity and ability to inhibit both ACE and α-amylase. CONCLUSIONS: Five of thirteen peptides identified in kiwicha protein digests show high potential to exert multifunctional properties. Thus kiwicha proteins might start to gain importance as ingredients for functional foods for the prevention and/or management of chronic diseases related to oxidative stress, hypertension and/or diabetes. © 2018 Society of Chemical Industry.