Background: ‘Legal highs’ began appearing in the UK in the mid-2000s. Whilst many of these substances were controlled under the 1971 Misuse of Drugs Act, novel compounds and new variants of controlled compounds were continuously being introduced to the recreational drug market. The Psychoactive Substances Act (PSA) was therefore implemented in 2016 as a blanket ban on all novel psychoactive substances (NPS). Aim: To evaluate the impact of the PSA on deaths following NPS use in England, Wales and Northern Ireland. Methods: Cases reported to the National Programme on Substance Abuse Deaths where death had occurred 3 years pre- or post-implementation of the PSA were extracted. Cases with NPS detected at post-mortem were analysed and compared against cases non-NPS cases. Results: 293 deaths with NPS detected were identified; 91 occurring before the PSA and 202 afterwards, indicating an 222.0% post-PSA increase. Contrastingly, non-NPS drug-related death case reporting increased by only 8.0%. Synthetic cannabinoid, anxiolytic/sedative and stimulant NPS were detected in the largest proportions of deaths pre-PSA; post-PSA stimulant NPS detections reduced whilst synthetic cannabinoid and anxiolytic/sedative detections increased. Post-PSA, average decedent age increased significantly (mean age pre-PSA 34.4 ± 10.8 vs post-PSA 38.3 ± 9.4), and they were significantly more likely to have been living in deprived areas (pre-PSA 50.0% vs post-PSA 65.9%). Conclusions: Reporting of deaths following NPS use has risen despite introduction of the PSA. Whilst deaths amongst younger individuals and those living in more affluent areas has reduced, additional approaches to prohibition are needed to curb their persistence in deprived demographics.