To assess the impact of the biological era on colectomy rates in ulcerative colitis (UC) patients and identify factors associated with the necessity for colectomy in a large cohort from Eastern Europe. A retrospective cohort study was conducted on UC patients followed at a tertiary care center covering 1999 to 2021. Patients who underwent colectomy due to disease activity were compared to those who did not. Factors related to colectomy and the influence of the biological era were analyzed. Among 1197 patients with a median follow-up of 3.3 years, 18% received biological agents and 5.3% underwent colectomy due to disease activity. The colectomy rate was lower in the biological era compared to the pre-biological era (2% vs. 12%; p < 0.001). Independent predictors of colectomy included steroid dependency, steroid resistance, lack of mucosal remission, and elevated CRP levels. Patients who achieved and maintained mucosal remission and had CRP levels below 3 mg/L had a significantly lower risk of colectomy. The biological era has significantly reduced colectomy rates in UC patients. Achieving mucosal remission and maintaining low CRP levels are essential for preventing colectomy and improving long-term outcomes.