Gabapentin is prescribed for pain and is perceived as safe generally. However, gabapentin can cause respiratory depression, exacerbated by concomitant central nervous system depressants (e.g., opioids), a concern for vulnerable populations. We compared mortality rates among new users of either gabapentin or duloxetine with or without concurrent opioids in the 20% Medicare sample. We conducted a new‐user design retrospective cohort study, in Medicare enrollees ages 65–89 years with noncancer chronic pain and no severe illness who filled prescriptions between 2015 and 2018 for gabapentin (n = 233,060) or duloxetine (n = 34,009). Daily opioid doses, estimated in morphine milligram equivalents (MMEs), were classified into none, low (0 < MME < 50), and high (≥ 50 MME), based on Centers for Disease Control and Prevention (CDC) recommendations. The outcomes were all‐cause mortality (primary) and out‐of‐hospital mortality (secondary). We used inverse probability of treatment weighting to adjust for differences between gabapentin and duloxetine users. During 116,707 person‐years of follow‐up, 1,379 patients died. All‐cause mortality rate in gabapentin users was 12.16 per 1,000 person‐years vs. 9.94 per 1,000 in duloxetine users. Risks were similar for users with no concurrent opioids (adjusted hazard ratio (aHR) = 1.03, 95% confidence interval (CI): 0.80–1.31) or low‐dose daily opioids (aHR = 1.06, 95% CI: 0.63–1.76). However, gabapentin users receiving concurrent high‐dose daily opioids had an increased rate of all‐cause mortality compared with duloxetine users on high‐dose opioids (aHR = 2.03, 95% CI: 1.19–3.46). Out‐of‐hospital mortality yielded similar results. In this retrospective cohort study of Medicare beneficiaries, concurrent use of high‐dose opioids and gabapentin was associated with a higher all‐cause mortality risk than that for concurrent use of high‐dose opioids and duloxetine.