Activating the cytoprotective response of nuclear factor erythroid 2-related factor 2 (Nrf2) can reduce oxidative stress and inflammation. A promising strategy is to inhibit the protein-protein interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2 using noncovalent compounds that target the Keap1 Kelch domain. These compounds may be more specific than covalent Keap1-reacting Nrf2 activators. However, the development of drug-like noncovalent Keap1-Nrf2 inhibitors faces challenges due to the size and polarity of the Kelch binding pocket. Here, we present a new series of noncovalent Keap1-Nrf2 inhibitors developed from a weak fragment hit identified by crystallographic screening. A two-step growing strategy and optimization guided by several X-ray cocrystal structures led to compounds with low nanomolar affinities and complete selectivity for Keap1 in a panel of homologous Kelch domains. In cells, compounds 24 and 28 potently activated the expression of Nrf2-controlled genes and showed anti-inflammatory effects by downregulating NLRP3 inflammasome and STING signalling activation. RNA sequencing revealed activation of cytoprotective pathways and a different profile from typical covalent Nrf2 activators. This work highlights the potential of fragment-based drug discovery for challenging targets like Keap1 and introduces novel Keap1-Nrf2 inhibitors as chemical probes and drug leads.