Abstract Background The treatment of inflammatory bowel disease (IBD) has evolved over the past two decades. Due to the recent introduction of multiple new biologics, it is crucial to understand the temporal patterns of drug change. This study aimed to examine the patterns of biological drug change over time and identify predictors of change in a cohort of patients with IBD. Methods We performed a retrospective study of patients diagnosed with IBD who were initiated on biologics and followed up at King Abdulaziz University (KAU) hospital, Jeddah, Saudi Arabia between June 2017, and October 2022. The KAUH inflammatory bowel disease information system (IBDIS) database was used to identify eligible patients. The study's primary objective was to describe biologics drug change patterns. Secondary outcomes included identifying predictors of drug change and time to discontinue biologics. Uni- and multi-variable odds ratios (ORs) were used to determine the predictors of drug change. Results A total of 910 patients who were registered in the IBDIS database were screened; 475 patients fulfilled the study criteria. 67% had CD, and 53.3% were males. The mean age at diagnosis was 22.6 (11.0) years. The most selected first and second choice of biologic was adalimumab (58.2% and 39.1%, p<0.001) and infliximab (37.6% and 48.9%, p=0.004) for both CD and UC, respectively. Ustekinumab was the primary third choice for CD (65.4%), while vedolizumab was the third choice for UC (83.3%). The proportions of patients who switched from first- and second-line adalimumab, infliximab, and vedolizumab were 52.3% and 20.9%, 37.6% and 39.9%, and 10.1% and 18.3%, respectively. On multiple regression analysis, a history of venous thromboembolism (VTE) (OR=3.60, 95% CI=1.20-11.71, p=0.025) and active smoking (OR=0.34, 95% CI=0.12-0.82, p=0.026) were associated with drug change for all patients. When stratified by disease subtype, drug change was associated with a diagnosis made between age 17 and 40 years (OR=0.46, 95% CI=0.23-0.90, p=0.024) and EIMs (OR=2.07, 95% CI=1.16-3.76, p=0.015) in CD while selecting vedolizumab as first biologic (OR=0.30, 95% CI=0.09-0.92, p=0.041), male gender (OR=2.40, 95% CI=1.04-5.73, p=0.043), and history of VTE (OR=7.32, 95% CI=0.23-49.97, p=0.031) were associated with drug change in UC. Conclusion Despite introducing several new biologics, anti-TNF therapies remain the preferred first and second choice of biologics for patients with IBD. The use of adalimumab is associated with the highest risk of switch. Multiple predictors of drug change over time exist for both diseases. The selection of vedolizumab as the first biologic for UC is associated with a lower risk of drug change.