Summary Background Colorectal cancer is one of the leading causes of cancer morbidity and mortality in Europe. We aimed to ascertain the economic burden of colorectal cancer across Europe using a population-based cost-of-illness approach. Methods In this population-based cost-of-illness study, we obtained 2015 activity and costing data for colorectal cancer in 33 European countries (EUR-33) from global and national sources. Country-specific aggregate data were acquired for health-care, mortality, morbidity, and informal care costs. We calculated primary, outpatient, emergency, and hospital care, and systemic anti-cancer therapy (SACT) costs, as well as the costs of premature death, temporary and permanent absence from work, and unpaid informal care due to colorectal cancer. Colorectal cancer health-care costs per case were compared with colorectal cancer survival and colorectal cancer personnel, equipment, and resources across EUR-33 using univariable and multivariable regression. We also compared hospital care and SACT costs against 2009 data for the 27 EU countries. Findings The economic burden of colorectal cancer across Europe in 2015 was €19·1 billion. The total non-health-care cost of €11·6 billion (60·6% of total economic burden) consisted of loss of productivity due to disability (€6·3 billion [33·0%]), premature death (€3·0 billion [15·9%]), and opportunity costs for informal carers (€2·2 billion [11·6%]). The €7·5 billion (39·4% of total economic burden) of direct health-care costs consisted of hospital care (€3·3 billion [43·4%] of health-care costs), SACT (€1·9 billion [25·6%]), and outpatient care (€1·3 billion [17·7%]), primary care (€0·7 billion [9·3%]), and emergency care (€0·3 billion [3·9%]). The mean cost for managing a patient with colorectal cancer varied widely between countries (€259–36 295). Hospital-care costs as a proportion of health-care costs varied considerably (24·1–84·8%), with a decrease of 21·2% from 2009 to 2015 in the EU. Overall, hospital care was the largest proportion (43·4%) of health-care expenditure, but pharmaceutical expenditure was far higher than hospital-care expenditure in some countries. Countries with similar gross domestic product per capita had widely varying health-care costs. In the EU, overall expenditure on pharmaceuticals increased by 213·7% from 2009 to 2015. Interpretation Although the data analysed include non-homogenous sources from some countries and should be interpreted with caution, this study is the most comprehensive analysis to date of the economic burden of colorectal cancer in Europe. Overall spend on health care in some countries did not seem to correspond with patient outcomes. Spending on improving outcomes must be appropriately matched to the challenges in each country, to ensure tangible benefits. Our results have major implications for guiding policy and improving outcomes for this common malignancy. Funding Department for Employment and Learning of Northern Ireland, Medical Research Council, Cancer Research UK, Health Data Research UK, and DATA-CAN.