Currently, there are no specific drugs for treating acute pancreatitis. Soluble epoxide hydrolase (sEH) inhibitors show promise, but face challenges like low blood drug concentrations and potential adverse effects on CYP enzymes and the human ether-a-go-go-related gene (hERG). In this study, an approach involving scaffold hopping and structure-activity guided optimization was employed to design a series of phenylquinoline-based sEH inhibitors. Among these compounds, DJ-53 exhibited potent in vitro and in vivo effects in alleviating pain and reducing inflammation. The in vivo mechanism of action involved inhibiting sEH enzyme activity, thereby increasing levels of anti-inflammatory epoxyeicosatrienoic acids (EETs) and decreasing levels of proinflammatory dihydroxyeicosatrienoic acids (DHETs). Importantly, DJ-53 showed exceptional oral bioavailability and pharmacokinetics, while avoiding inhibition of CYP enzymes or the hERG channel. These results highlight DJ-53's potential as a new lead compound for anti-inflammatory and analgesic applications and provide a safe and effective scaffold for developing sEH inhibitors.