BackgroundPrescribing of strong opioids and antibiotics impacts patient safety, yet little is known about the effects GP wellness has on overprescribing of both medications in primary care.AimTo examine associations between strong opioid and antibiotic prescribing and practice- weighted GP burnout and wellness.Design and settingA retrospective cross-sectional study was undertaken using prescription data on strong opioids and antibiotics from the Oxford- Royal College of General Practitioners Research and Surveillance Centre linking to a GP wellbeing survey overlaying the same 4-month period from December 2019 to April 2020.MethodPatients prescribed strong opioids and antibiotics were the outcomes of interest.ResultsData for 40 227 patients (13 483 strong opioids and 26 744 antibiotics) were linked to 57 practices and 351 GPs. Greater strong opioid prescribing was associated with increased emotional exhaustion (incidence risk ratio [IRR] 1.19, 95% confidence interval [CI] = 1.10 to 1.24), depersonalisation (IRR 1.10, 95% CI = 1.01 to 1.16), job dissatisfaction (IRR 1.25, 95% CI = 1.19 to 1.32), diagnostic uncertainty (IRR 1.12, 95% CI = 1.08 to 1.19), and turnover intention (IRR 1.32, 95% CI = 1.27 to 1.37) in GPs. Greater antibiotic prescribing was associated with increased emotional exhaustion (IRR 1.19, 95% CI = 1.05 to 1.37), depersonalisation (IRR 1.24, 95% CI = 1.08 to 1.49), job dissatisfaction (IRR 1.11, 95% CI = 1.04 to 1.19), sickness–presenteeism (IRR 1.18, 95% CI = 1.11 to 1.25), and turnover intention (IRR 1.38, 95% CI = 1.31 to 1.45) in GPs. Increased strong opioid and antibiotic prescribing was also found in GPs working longer hours (IRR 3.95, 95% CI = 3.39 to 4.61; IRR 5.02, 95% CI = 4.07 to 6.19, respectively) and in practices in the north of England (1.96, 95% CI = 1.61 to 2.33; 1.56, 95% CI = 1.12 to 3.70, respectively).ConclusionThis study found higher rates of prescribing of strong opioids and antibiotics in practices with GPs with more burnout symptoms, greater job dissatisfaction, and turnover intentions; working longer hours; and in practices in the north of England serving more deprived populations.