Abstract Purpose Changes in plasma volume (PV), acid–base status and ventilation have rarely been investigated in relation to resistance training (RT). This study aimed to investigate the effect of a single set of exhaustive leg press exercise on these basic physiological parameters in an integrated manner. Methods Twenty-seven male individuals (27.1 ± 4.1 years, 1.82 ± 0.62 m, 84.4 ± 12.5 kg, BMI: 25.4 ± 3.0 k/gm2) performed a single set leg press exercise during which hemoglobin concentration ([Hb]), hematocrit (Hct), pH, oxygen (pO2) and carbon dioxide partial pressures (pCO2), hydrogen carbonate concentration ([HCO3−]), standard base excess (SBE) and lactate concentration ([La−]) were determined. Total buffer capacity was calculated based on pH, [HCO3−] and pCO2. Results Mean PV decreased by 559 ± 230 mL (13.7%). As a result, arterial oxygen content was significantly increased due to hemoconcentration (P < 0.001). At exhaustion, pH (7.30 ± 0.06), [HCO3−] (18.6 ± 2.0 mmol/L) and SBE (− 6.6 ± 2.4 mmol/L) were all significantly decreased (P < 0.0001). The pCO2 first remained unchanged (39.4 ± 4.3 mm Hg) but demonstrated a significant decrease one-minute post-exercise (34.4 ± 4.2 mmHg), indicating metabolic acidosis with respiratory compensation, which was maintained until t+15. Non-bicarbonate buffering remained constant during recovery while the respiratory component steadily increased until 15-min post-exercise (50.2 mmol/L per pH). Conclusion PV shifts following a single set of leg press exercise improve post-exercise arterial oxygen content. The moderate metabolic acidosis was not compensated during exercise because of restricted breathing but partly compensated during the following 15-min recovery period. The respiratory compensation as part of the bicarbonate buffering made up 50% of total buffer capacity in the course of recovery.