Background: Baicalin is considered to be able to alleviate the progression of ulcerative colitis (UC), but the underlying molecular mechanism needs to be further elucidated. Methods: TNF-alpha-induced human normal colorectal mucosa cells (FHC) were used to mimic UC models in vitro , and trinitrobenzene sulfonic acid (TNBS)-injected rats were used to construct UC models in vivo . Cell proliferation and apoptosis were determined by CCK8 assay, EdU assay and flow cytometry. Inflammation factors were examined by ELISA, and ferroptosis-related markers were detected by corresponding kit. The mRNA and protein levels of solute carrier family 6 member 14 (SLC6A14) and specific protein 1 (SP1) were analyzed by qRT-PCR and western blot. The interaction between SP1 and SLC6A14 promoter was verified by ChIP assay and dual-luciferase reporter assay. Results: Baicalin enhanced proliferation, while repressed apoptosis, inflammation, and ferroptosis in TNF-alpha-induced FHC cells. SLC6A14 was upregulated in UC patients, and baicalin could decrease SLC6A14 expression. SLC6A14 overexpression reversed the inhibitory effect of baicalin on TNF-alpha-induced FHC cell injury. SP1 could bind to SLC6A14 promoter region to upregulate its expression, and ectopic expression of SLC6A14 also abolished the suppressive effect of SP1 knockdown on TNF-alpha-induced FHC cell injury. Baicalin reduced SP1 expression to downregulate SLC6A14. In addition, baicalin alleviated UC process in vivo via repressing inflammation, and ferroptosis. Conclusion: Baicalin repressed SP1-mediated transcription of SLC6A14 to restrain cell apoptosis, inflammation, and ferroptosis, thus alleviating UC progression.