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Introduction Despite warnings from the US Food and Drug Administration about respiratory adverse events associated with gabapentinoids, direct evidence of their risk in patients with asthma is lacking.Methods Using a national administrative claims database, we prepared two active comparators—new user cohorts of patients with a history of neuropathic or chronic pain and asthma—initiating gabapentinoids and comparator drugs (tricyclic antidepressants (TCAs) or serotonin norepinephrine reuptake inhibitors (SNRIs)). Overlap propensity score weighting was used to control for potential confounders. The initial occurrence of asthma exacerbation requiring systemic corticosteroids (primary) or those requiring hospitalisation for asthma (secondary) was assessed using a weighted Cox proportional hazards model.Findings In the TCAs cohort (171 393 gabapentinoids users and 5916 TCAs users), gabapentinoids use was associated with a higher incidence of primary (59.4 vs 33.7 per 100 person-years; HR 1.46, 95% CI 1.34 to 1.60) and secondary outcomes (0.91 vs 0.42 per 100 person-years; 2.02, 1.11 to 3.68). In the SNRIs cohort (189 055 gabapentinoids users and 19 800 SNRIs users), using gabapentinoids was also associated with a higher incidence of primary outcome (63.5 vs 42.8 per 100 person-years; HR 1.24, 1.19 to 1.30). However, the difference in the secondary outcome did not reach statistical significance (0.93 vs 0.68 per 100 person-years; 1.24, 0.94 to 1.63).Interpretation Gabapentinoids were associated with an increased risk of asthma exacerbations compared with TCAs or SNRIs. Managing neuropathic or chronic pain in patients with asthma using gabapentinoids should be approached with caution.