Research exploring the role of frustration response as a risk factor for irritability in autistic populations is limited and often uses parent report or observer ratings; objective measures of frustration response appropriate for use in autistic people are required to advance the field. For a study, the researchers, 52 autistic adolescents aged 13–17 years from a longitudinal population-based survey completed an experimental task designed to induce frustration through exposure to periods of an unexpected delay. Analyses showed a marginal relation between irritability and the slope of behavioral response (Incident Rate Ratio (IRR)=.98, P=.06), and significant relation with the hill of physiological response (b=−.10, P=.04); increased levels of irritability were related with a dampened behavioral and physiological response, as indicated by flatter slopes of change throughout the task. The pattern of results largely remained in sensitivity analyses, although the relation with physiological response became non-significant when adjusting for IQ, autism symptom severity, and medication use (b=−.10, P=.10). Results suggested that the experimental task may be a useful objective measure of frustration response for use with autistic populations and that a non-adaptive response to frustration may be one biological mechanism underpinning irritability in autistic youth. This might have represented an important target for future intervention practice.