Background: The present study examined the effect of a micro-dose of resistance-exercise on serum DHEA-S, IL-6 and mood-state determinants. Potential relationships between mood and the biomarkers were also studied with the aim of directing research on non-invasive exercise-monitoring methods. Methods: 30 male participants (20 weightlifting-trained; 10 untrained) were separated into 3 groups of 10: weightlifting experimental (WLEXP); untrained experimental (UTEXP); weightlifting placebo (WLPLA). WLEXP and UTEXP performed four 60-s isometric thumb exertions separated by 60-s rest intervals in a single-blinded placebo-controlled study. Participants were assessed over a 60-min post-intervention recovery period for changes in serum DHEA-S and IL-6, and mood-state determinants (vigour, tension, fatigue). Results: DHEA-S changed in UTEXP only; a decrease from 20- to 60-min post-exercise (Δ36.9 %, p < 0.01). DHEA-S remained below baseline at the final time-point (Δ35.3 %, p = 0.012). Tension decreased immediately post-exercise in WLEXP (Δ86.7 %, p = 0.022), whereas UTEXP showed a delayed decrease which continued up to 60-min post-intervention (Δ100 %, p < 0.01). Relative to fatigue scores recorded immediately post-exercise, WLEXP decreased within the first 10-min post-intervention (Δ22.2 %, p < 0.01) whereas UTEXP showed a delayed decrease evident at 20-min post-intervention (Δ25 %, p < 0.01). Serum IL-6 and vigour scores remained unchanged across groups (p > 0.05) and WLPLA did not change for any measured variable (p > 0.05). Conclusions: The authors conclude that a micro-dose of resistance-exercise can reduce serological DHEA-S concentration within 60-min of exercise cessation. Additionally, mood-state assessment in untrained individuals can be considered for non-invasively indicating exercise-induced concentration changes in the stress biomarker, DHEA-S, providing prospects for the development of safer, more sophisticated exercise-monitoring practice.