Colorectal cancer (CRC) represents a global public health concern. CRC screening is associated with significant reductions in CRC incidence and mortality, however, uptake is suboptimal. This systematic review and meta-analysis of randomised controlled trials explored the effectiveness of interventions designed to increase screening uptake, plus the impact of various moderators. Data from 102 studies including 1.94 million participants were analysed. Results showed significant benefit of all interventions combined (OR, 1.49, 95% CI: 1.43, 1.56, p < 0.001). The effects were similar in studies using objective versus self-reported uptake measures and lower in studies judged to be at high risk of bias. Moderator analyses indicated significant effects for aspects of behaviour (effects lower for studies on non-endoscopic procedures), and intervention (effects higher for studies conducted in community settings, in healthcare systems that are not free, and that use reminders, health-professional providers, paper materials supplemented with in-person or phone contact, but avoid remote contact). Interventions that included behaviour change techniques targeting social support (unspecified or practical), instructions or demonstration of the behaviour, and that added objects to the environment produced stronger effects. The way in which findings can inform interventions to improve CRC screening uptake is discussed.