G protein-coupled receptors (GPCRs) play pivotal roles in converting physicochemical stimuli due to environmental changes to intracellular responses. After ligand stimulation, many GPCRs are desensitized and then recycled or degraded through b-arrestin-dependent internalization, an important process to maintain protein quality control of GPCRs. However, it is unknown how GPCRs with low β-arrestin sensitivity are controlled. Here we unmasked a b-arrestin-independent GPCR internalization, named Redox-dependent alternative internalization (REDAI), using b-arrestin-resistant purinergic P2Y₆ receptor (P2Y₆R). Natural isothiocyanates (ITCs) covalently bind with Cys²²⁰ in the intracellular 3^rd loop of P2Y₆R, and promote internalization and degradation of P2Y₆R through ubiquitination of Lys¹³⁷ in the 2^nd loop. P2Y₆R is highly expressed in macrophage and pathologically contributes to the development of colitis in mice. Endogenous electrophiles, such as S-nitrosoglutathione, also induce P2Y₆R degradation leading to anti-inflammation in macrophages. Prevention of Cys²²⁰ modification on P2Y₆R resulted in aggravation of the colitis. Accordingly, targeting REDAI on GPCRs will be a breakthrough strategy for the prevention and treatment of inflammatory diseases.