Crocin, a water-soluble carotenoid, is known as a pharmacologically active compound, particularly for its potent anti-oxidant activity. The present work provides a comprehensive review of the available literature concerning the anti-inflammatory properties of crocin in various organs/systems as well as its anti-nociceptive effects. PubMed, Scopus, and Web of Science electronic databases were systematically searched up to 28 March 2020 to detect all relevant preclinical and human studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. In total, 104 studies were included for qualitative synthesis. This systematic search and review indicated that crocin not only combats reactive oxygen species production and suppresses pro-inflammatory cytokines secretion but also alleviates inflammation in various organs (e.g. the lung, heart, brain, and kidney), in a series of animal models and in vitro experiments, via regulating mainly NF-κB pathway and NF-κBp65 translocation to the cell nucleus. In this context, modulation of PI3K/Akt appears to be a favorable crocin target contributing to NF-κB pathway inhibition. Even though data is limited in humans with only one clinically relevant study retrieved, the results of preclinical studies regarding anti-inflammatory/anti-nociceptive effects of crocin are promising and warrant further testing in clinical settings. Display omitted •Crocin anti-inflammatory function involves suppression of MAPK and NF-kB, but activation of Nrf2.•Crocin decreases secretion of TNF-α, IL-6, IL-10, IFN-γ and IL-1β (in vitro/in vivo) and reduces TNF-α and IL-17 in humans.•Suppression of MAPK and Wnt5α/β-catenin signaling mediates crocin pain killing effects.•Crocin’s anti-inflammatory/anti-nociceptive effects are promising and warrant further testing in clinical settings.