BACKGROUND: This preregistered functional magnetic resonance imaging study aimed to test and possibly extend the triple network hypothesis of psychosocial stress processing, positing that responses in the salience network (SN) and the default mode network (DMN) dominate at the expense of the central executive network (CEN). Furthermore, we tested the hypothesis that stress-related responses in SN and DMN structures are associated with hormonal, cardiovascular, and affective stress responses, while CEN and DMN structures are associated with task performance. We also examined sex-specific associations between neural and stress-induced cortisol, heart rate, and negative affect responses as well as task performance. METHODS: We reviewed all psychosocial stress studies and conducted a mega-analysis of ScanSTRESS datasets (n = 459; 222 female) with harmonized preprocessing. RESULTS: Our findings advanced the original hypothesis, revealing activations and deactivations across all 3 networks, related in a complex way to cortisol, heart rate, negative affect, and performance parameters. Additionally, we identified a novel age effect of increasing DMN activation with age, replicated an exposure-time effect of decreasing activation with duration, showed sex-specific patterns, and confirmed the involvement of all networks by task-based connectivity analyses. CONCLUSIONS: Based on our findings we suggest a new, differentiated triple network hypothesis of psychosocial stress processing. Reactivity in SN and DMN structures is associated with hormonal, cardiovascular, and affective stress responses, whereas CEN and DMN structures process the stress-eliciting tasks. Moreover, the age effect may indicate that the ability to downregulate the DMN is reduced with age. Finally, we suggest that the exposure-time effect (decreasing signal within ScanSTRESS) may be a promising resilience biomarker.