Objective The incidence of colorectal cancer (CRC) remains elevated in the inflammatory bowel disease (IBD) population. We aimed to examine the association of biologics, 5-aminosalicylates (5-ASAs) and immunomodulators with the risk of CRC and/or dysplasia (CRC/Dys) in different IBD phenotypes. Methods We searched Web of Science, PubMed, MEDLINE and EMBASE from inception to 15 March 2025 for all studies assessing the association of biologics, 5-ASAs and immunomodulators on the occurrence of CRC/Dys in adults (≥16 years) with IBD. No randomised controlled trials were identified. Data were pooled using a random effects model generating relative risk (RR) estimates. Results Fifty observational studies containing 29 325 cases of CRC/Dys in 1 434 939 patients with IBD were included. Biologic therapies (RR 0.74; 95% CI 0.64 to 0.85, I 2 =56.8%) and 5-ASAs (RR 0.78; 95% CI 0.70 to 0.86, I 2 =52.1%) were associated with a reduced risk of CRC/Dys in patients with IBD. Immunomodulators were not associated with a reduced risk (RR 0.92; 95% CI 0.82 to 1.02, I 2 =82.7%). After stratification for IBD phenotypes, medication subgroups and CRC outcome, anti-tumour necrosis factor (anti-TNF) therapies were associated with a reduced risk of CRC in patients with ulcerative colitis (RR 0.78; 95% CI 0.73 to 0.83, I 2 =0%) but not in Crohn’s disease. Non-sulfasalazine 5-ASAs were associated with a reduced risk of CRC in ulcerative colitis (RR 0.66; 95% CI 0.45 to 0.96, I 2 =75.4%) and Crohn’s disease (RR 0.84; 95% CI 0.81 to 0.87, I 2 =41.9%). Conclusion Use of anti-TNF biologics or non-sulfasalazine 5-ASAs is associated with a reduction in CRC risk in IBD, with differential effects by IBD phenotype. PROSPERO registration number CRD42024559501.