Objective To assess the prevalence and potential risk factors for polypharmacy and prescribing of the potentially inappropriate medications, opioids and benzodiazepines/Z‐drugs, in older adults with systemic lupus erythematosus (SLE). Methods The study population comprised adults age ≥50 years meeting American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria followed at a tertiary care rheumatology clinic. Information on prescriptions filled in the 4 months preceding chart review was obtained from the Manitoba Drug Program Information Network. Clinical data, including age, sex, Charlson Comorbidity Index (CCI) score, Systemic Lupus Erythematosus Disease Activity Index 2000 score, prednisone use, SLE duration, and rural residence were abstracted from electronic medical records. Logistic regression analyses were performed to assess any association between polypharmacy (using 2 definitions: ≥5 and ≥10 medications), potentially inappropriate medication use, and clinical features. Results A total of 206 patients (mean age 62 years, 91% female, 36% rural) were included: 148 (72%) filled ≥5 medications, 71 (35%) filled ≥10 medications, 63 (31%) used benzodiazepines/Z‐drugs, and 50 (24%) used opioids. Among the 77 patients age ≥65 years, 57 (74%) filled ≥5 medications, and 26 (34%) filled ≥10 medications, compared to 30% and 4%, respectively, of Manitobans age ≥65 years (National Prescription Drug Utilization Information System, 2016). The odds of polypharmacy were greater with prednisone use (adjusted odds ratio [OR] 3.70 [95% confidence interval (95% CI) 1.40–9.79] for ≥5 medications), CCI score (adjusted OR 1.62 [95% CI 1.20–2.17]), and rural residence (adjusted OR 2.05 [95% CI 1.01–4.18]). Odds of benzodiazepine/Z‐drug use were increased with polypharmacy (adjusted OR 4.35 [95% CI 1.69–11.22]), and odds of opioid use were increased with polypharmacy (adjusted OR 6.75 [95% CI 1.93–23.69]) and CCI score (adjusted OR 1.29 [95% CI 1.08–1.54]). Conclusion The prevalence of polypharmacy in this SLE cohort was higher than in the general Manitoban population. Polypharmacy is a strong marker for use of prescription benzodiazepines/Z‐drugs and opioids.