Background: Rapid symptom control is critical in managing ulcerative colitis (UC), especially in patients with severe disease. While multiple advanced therapies (AT) are approved for moderate to severe UC, data comparing their speed of onset are limited. We compared the onset and induction efficacy of ATs for UC among biologic-naïve patients with severe endoscopic disease (Mayo endoscopic subscore [MES] of 3) and explored differential responses in patients with moderate (MES 2) versus severe endoscopic disease. Methods: This was a post-hoc analysis using individual participant-level data from 11 randomized controlled trials. Biologic-naïve patients with MES 3 disease receiving standard induction regimens of infliximab, adalimumab, golimumab, vedolizumab, ustekinumab, mirikizumab, tofacitinib, or upadacitinib were included. The primary outcome was early PRO-2 response, defined as ≥50% reduction in stool frequency and rectal bleeding scores at two weeks post-baseline. Secondary outcomes included post-induction clinical remission and PRO-2 remission. Logistic regression models adjusted for baseline covariates were used. Results: A total of 1781 biologic-naïve patients with MES 3 disease were included. Infliximab (35.1%) and upadacitinib (32.4%) demonstrated the highest early PRO-2 response rates. Compared to placebo, the highest odds of response were observed with upadacitinib [adjusted odds ratio (aOR): 6.38 (95% CI: 2.11-19.23), p=0.001] and infliximab [aOR 4.49 (95% CI: 2.05-9.85), p<0.001]. At post-induction, infliximab (72.2%) and upadacitinib (59.5%) again demonstrated superior PRO-2 response rates. In comparison to MES 2 patients, those with MES 3 had reduced odds of early and post-induction response for several therapies, particularly ustekinumab, tofacitinib, vedolizumab, and mirikizumab. Conclusions: Among biologic-naïve UC patients with severe endoscopic disease, infliximab and upadacitinib had the highest rates of week 2 and post-induction PRO-2 response. Baseline disease activity may help to better inform treatment choices.