Background/Objectives: Therapeutic management of inflammatory bowel diseases (IBD) is rapidly evolving in the era of novel biological therapies. However, real-world data relating to the usage trends and treatment persistence remain inconsistent. This study aimed to investigate trends in biological use, dose intensification, and treatment persistence in IBD patients, who received treatment in a large tertiary center in Greece. Methods: Patients with IBD who underwent at least one biological treatment between 2018 and 2022 were included in this retrospective study. Data on patients' demographics, type of disease, use of biologicals, dose intensification, and treatment persistence were analyzed for time trends. Results: Data from 409 patients with IBD (mean age 39 (range 17-87), female 51%, 56.9% CD, mean duration of disease: 9.3 years) were included in the study. The number of patients on biologics was raised from 133 in 2018 to 368 in 2022 (a 28.1% yearly increase), while the percentage of patients who were treated with anti-TNF biosimilars increased to >60% of the total anti-TNF population in 2022. We observed a gradual increase in non-anti-TNF therapies in bio-na & iuml;ve patients, in particular vedolizumab (46% of all biologicals in UC; 16% in CD) and ustekinumab (16.3% of all biologicals in UC, 31% in CD). The 3-year persistence rate of IFX was 64% in CD and 56% in UC, whereas it was 61% for ADA in CD. Dose intensification of anti-TNF was efficient in >50% of CD patients and >30% of UC patients; however, the majority of patients who required dose escalation within the first year eventually became unresponsive. The 3-year persistence of vedolizumab as a first-line treatment was 82% for CD and 69% for UC, respectively. The 3-year persistence of ustekinumab as first-line treatment for CD was 65%. No significant differences regarding the efficacy of anti-TNF, ustekinumab, or vedolizumab were detected when they were used as first-line treatments for Crohn's disease; similarly, no significant differences were detected between infliximab and vedolizumab as first-line treatments for UC. Conclusions: There was a gradual increase in the use of biologicals, including biosimilars, between the years 2018-2022, reflecting adherence to current guidance with adoption of an early escalation strategy. Newer, post-anti-TNF biologics such as vedolizumab and ustekinumab have been rapidly incorporated into therapeutic approaches for both CD and UC.