Ulcerative colitis (UC), a chronic relapsing inflammatory bowel disease, is typified by cycles of remission and acute flare-ups. Predicting these exacerbations is clinically challenging, necessitating reliable, non-invasive biomarkers for early detection. This study investigates the diagnostic utility of serum C-reactive protein (CRP) and fibrinogen levels in forecasting UC flare-ups. A total of 120 patients with histologically confirmed UC were enrolled and divided into two cohorts: those experiencing active flares and those in remission. Serum CRP and fibrinogen levels were analyzed and correlated with Mayo scores and endoscopic findings. Results revealed significantly higher concentrations of CRP (p < 0.001) and fibrinogen (p = 0.002) in the flare group. Receiver operating characteristic (ROC) analyses demonstrated that both biomarkers had strong predictive value, with CRP outperforming fibrinogen in sensitivity and specificity. These findings support the clinical relevance of CRP and fibrinogen as adjunctive tools for early detection and proactive management of UC flare-ups, potentially reducing dependence on invasive diagnostics like endoscopy.