The epidemiology of colorectal cancer (CRC) has changed rapidly over the years. The aim of this study was to assess the trends in incidence, treatment, and relative survival (RS) of patients diagnosed with CRC in the Netherlands between 2000 and 2021. 2 75667 patients diagnosed with CRC between 2000 and 2021 were included from the Netherlands Cancer Registry. Analyses were stratified for disease extent (localised: T1-3N0M0; regional: T4N0M0/T1-4N1-2M0; distant: T1-4N0-2M1) and localisation (colon; rectum). Trends were assessed with joinpoint regression. CRC incidence increased until the mid-2010s but decreased strongly thereafter to rates comparable with the early 2000s. Amongst other trend changes, local excision rates increased for patients with localised colon (2021: 13.6 %) and rectal cancer (2021: 34.9 %). Moreover, primary tumour resection became less common in patients with distant colon (2000–2021: 60.9–12.5 %) or rectal cancer (2000–2021: 47.8–6.9 %), while local treatment of metastases rates increased. Five-year RS improved continuously for localised and regional colon (97.7 % and 72.0 % in 2017, respectively) and rectal cancer (95.2 % and 76.3 % in 2017, respectively). The rate of anti-cancer treatments decreased in distant colon (2010–2021: 80.3 % to 67.2 %; p < 0.001) and rectal cancer (2011–2021: 86.0 % to 77.0 %; p < 0.001). The improvement of five-year RS stagnated for distant colon (2010–2017: 11.2 % to 11.9 %; average percentage of change APC: 2.1, 95 % confidence interval CI: −7.6, 4.7) and rectal cancer (2009–2017: 12.7 % to 15.6 %; APC: 1.4, 95 % CI: −19.1, 5.5). Major changes in the incidence and treatment of CRC between 2000 and 2021 were identified and quantified. Five-year RS increased continuously for patients with localised and regional CRC, but stagnated for patients with distant CRC, likely caused by decreased rates of anti-cancer treatment in this group. •Clinical practice for colorectal cancer (CRC) has changed vastly in recent years.•The incidence of CRC has decreased rapidly since population screening.•Rates of anti-cancer treatment decreased for distant CRC since approximately 2010.•Relative survival increased for localised and regional CRC during the study.•For distant CRC, relative survival did not increase since approximately 2010.