Abstract Background People with a cancer signal detected via multi-cancer early detection (MCED) screening need timely access to confirmatory diagnostic testing. We estimated the likely change in demand for diagnostic testing in England if MCED screening were introduced. Methods Diagnostic demand was modelled based on (1) estimates of the volume of people aged 50–79 years who would be referred for diagnostic investigation following a ‘cancer signal detected’ result after MCED screening and (2) MCED test performance metrics. Predicted usage was compared with current annual usage using routine NHS datasets. Results In an established MCED screening programme, assuming 70% of the total eligible population is screened annually (~13 million), the relative change in diagnostic demand was greatest for colonoscopy (+2.09%; +13,730 each year); the greatest absolute change was for computed tomography (CT; +0.76%; +62,320). This equates to +1040 colonoscopies and +4720 CT scans for every million screened. Conclusions The predicted relative increase in diagnostic testing generated by MCED screening is small, though a large eligible population and maximum uptake could translate into a large number of procedures. Cancer diagnoses brought forward in time through screening should reduce diagnostic use for symptomatic presentations in the future.