Background and Aims Research has shown that internet interventions can be effective for dependent users of various substances. However, less is known about the effects of these interventions on users of opioids, cocaine and amphetamines than for other substances. We aimed to investigate the effectiveness of internet interventions in decreasing the usage of these types of substances. Methods We conducted a systematic literature search in the databases of PubMed, PsycINFO, Embase and the Cochrane Library to identify randomized controlled trials examining the effectiveness of internet interventions compared with control conditions in reducing the use of opioids, cocaine and amphetamines. No setting restrictions were applied. The risk of bias of the included studies was examined according to the Cochrane Risk of Bias assessment tool. The primary outcome was substance use reduction assessed through toxicology screening, self-report or both at post-treatment and at the follow-up assessment. Results Seventeen studies with 2836 adult illicit substance users were included. The risk of bias varied across the included studies. Internet interventions decreased significantly opioid [four studies, n = 606, g = 0.36; 95% confidence interval (CI) = 0.20–0.53, P < 0.001] and any illicit substance use (nine studies, n = 1749, g = 0.35; 95% CI = 0.24–0.45, P < 0.001) at post-treatment. Conversely, the effect of internet intervention for stimulant users was small and non-significant (four studies, n = 481, P = 0.164). Overall, internet interventions decreased substance significantly use at post-treatment (17 studies, n = 2836, g = 0.31; 95% CI = 0.23–0.39, P < 0.001) and at the follow-up assessments (nine studies, n = 1906, g = 0.22; 95% CI = 0.07–0.37; P = 0.003). Conclusions Internet interventions demonstrate small but significant effects in decreasing substance use among various target populations at post-treatment and at the follow-up assessment. However, given the small number of available studies for certain substances, the findings should be interpreted with caution.