Oral administration, while convenient, but complex often faces challenges due to the complexity of the digestive environment. In this study, we developed a nanoliposome (NLP) encapsulating psoralen (P) and coated it with chitosan (CH) and pectin (PT) to formulate PT/CH-P-NLPs. PT/CH-P-NLPs exhibit good biocompatibility, superior to liposomes loaded with psoralen and free psoralen alone. After oral administration, PT/CH-P-NLPs remain stable in the stomach and small intestine, followed by a burst release of psoralen after reaching the slightly alkaline and gut microbiota-rich colon segment. In the DSS-induced ulcerative colitis of mice, PT/CH-P-NLPs showed significant effects on reducing inflammation, mitigating oxidative stress, protecting the integrity of the colon mucosal barrier, and modulating the gut microbiota. In conclusion, the designed nanoliposomes demonstrated the effective application of psoralen in treating ulcerative colitis.