Aims To assess the effectiveness for Scotland's National Naloxone Programme (NNP) by comparison between 2006–10 (before) and 2011–13 (after NNP started in January 2011) and to assess cost‐effectiveness. Design This was a pre–post evaluation of a national policy. Cost‐effectiveness was assessed by prescription costs against life‐years gained per opioid‐related death (ORD) averted. Setting Scotland, in community settings and all prisons. Intervention Brief training and standardized naloxone supply became available to individuals at risk of opioid overdose. Measurements ORDs as identified by National Records of Scotland. Look‐back determined the proportion of ORDs who, in the 4 weeks before ORD, had been (i) released from prison (primary outcome) and (ii) released from prison or discharged from hospital (secondary). We report 95% confidence intervals for effectiveness in reducing the primary (and secondary) outcome in 2011–13 versus 2006–10. Prescription costs were assessed against 1 or 10 life‐years gained per averted ORD. Findings In 2006–10, 9.8% of ORDs (193 of 1970) were in people released from prison within 4 weeks of death, whereas only 6.3% of ORDs in 2011–13 followed prison release (76 of 1212, P < 0.001; this represented a difference of 3.5% 95% confidence interval (CI) = 1.6–5.4%). This reduction in the proportion of prison release ORDs translates into 42 fewer prison release ORDs (95% CI = 19–65) during 2011–13, when 12 000 naloxone kits were issued at current prescription cost of £225 000. Scotland's secondary outcome reduced from 19.0 to 14.9%, a difference of 4.1% (95% CI = 1.4–6.7%). Conclusions Scotland's National Naloxone Programme, which started in 2011, was associated with a 36% reduction in the proportion of opioid‐related deaths that occurred in the 4 weeks following release from prison.