Background and objectives <p>Remote ischemic preconditioning (RIPC) diminishes multi-organ failure induced by skeletal muscle ischemia and reperfusion (S-I/R). The current study investigated whether skeletal RIPC protection against S-I/R-induced acute lung injury (ALI) could be facilitated following simultaneous exposure to the glycoprotein hormone erythropoietin (EPO) in rats and whether this interaction is modulated by the NLRP3 inflammasome. </p> Methods <p>S-I/R challenge was performed by 3-h ischemia followed by 3-h reperfusion of the right hindlimb, whereas RIPC involved three 20-min brief consecutive I/R cycles of the contralateral hindlimb.</p> Results <p>The lung injurious response to S-I/R was verified by: (i) decreases in minute respiratory volume (MRV), forced expiratory volume 1 (FEV1) and functional vital capacity (FVC), (ii) increases in respiratory rate (RR), (iii) falls in lung surfactant protein-D (SP-D) and rises in of lung plasminogen activator inhibitor-1 (PAI-1) and intercellular adhesion molecule-1 (ICAM-1), and (iv) disruption of alveolar architecture. These lung defects were partially amended by RIPC or EPO (500 or 5000&#xa0;IU/kg). Further, the prior exposure to RIPC plus EPO-500 was more effective than separate interventions in rectifying ALI damages. Molecularly, the dual RIPC/EPO-500 regimen was also more effective in reversing the S-I/R-associated increments in pulmonary expressions of NLRP3 and related inflammatory (TLR4, MyD88, TRAF, NF-κB, TNF-α, IL-1β, and IL-18), apoptotic (ASC, procaspse-1, caspase-1), and microRNA signals (increases in miR-21 and decreases miR-495).</p> Conclusion <p>These findings suggest a pivotal role for the suppression of NLRP3 inflammasome and interconnected cellular offenses in the augmented therapeutic potential of the RIPC/EPO-500 regimen against S-I/R-induced ALI.</p>