Purpose <p>To determine the effectiveness of integrating a web-based tool into hospital pharmacist medication optimization activities on high-risk medication use and explore implementation.</p> Methods <p>An implementation study with retrospective control group. The intervention consisted of multi-step pharmacist-led medication review using The Drug Burden Index (DBI) Calculator© implemented on four wards. Patients aged ≥ 70&#xa0;years admitted on one or more medications with anticholinergic or sedative properties were eligible to participate. Primary outcome was change in DBI score and secondary outcomes included safety (adverse drug withdrawal events), feasibility (pharmacist time) and fidelity (whether intervention elements were conducted). Implementation was explored through mixed methods: post-intervention interviews with participants/caregivers, pharmacists and prescribers, and subgroup analyses.</p> Results <p>Data were analyzed from 148 retrospective control and 40 intervention participants. Participants were median 79 (interquartile range = 12) years old and 61% were female. A meaningful reduction in DBI score (≥ 0.5) occurred in 23% (9/40) of intervention versus 6% (9/158) of control group (<i>p</i> = 0.003). No adverse drug withdrawal events occurred in the intervention group. Pharmacists took an average of 68&#xa0;min to complete all intervention elements. Interviews (<i>n</i> = 13) confirmed that the DBI Calculator© supported deprescribing although several barriers remained, including a need for incorporation of tools into the electronic medical record and protected time for pharmacists on the wards for clinical activities.</p> Conclusion <p>Integrating The DBI Calculator© into pharmacist-led medication reviews supported deprescribing efforts and was effective at reducing the DBI score in older hospital inpatients. Further research is required to explore widespread implementation and sustainability.</p> Trial registration <p>Clinicaltrials.gov NCT03698487, registered 2018–10-09.</p>