PURPOSE: Lower extremity ischemia-reperfusion injury (IRI) triggers systemic inflammation and oxidative stress, causing myocardial remote ischemia-reperfusion injury (MIRI). Current treatments are limited. METHODS: Male Sprague-Dawley rats (n = 6 per group) were assigned to Sham, I/R, I/R + colchicine (C), I/R + HBOT, and I/R + HBOT + C. IRI was induced by 60-min infrarenal aortic clamping and 120-h reperfusion. TREATMENT: Once daily colchicine (0.3 mg/kg) and HBOT (2.5 ATA, 100% O2) twice daily were administered for 5 days post-reperfusion. Cardiac damage, oxidative stress, inflammation, and NRF-2/HO-1 signaling were measured, and electrocardiography (ECG) was performed. RESULTS: I/R caused severe MIRI (Hs-Troponin T: 568.54 pg/mL; heart OSI: 20.98; TNF-α: 582.89 pg/mL). Both monotherapies reduced damage, but HBOT + C was superior: Hs-Troponin T 342.07 pg/mL, OSI 2.26, TNF-α 278.82 pg/mL, and IL-6 12.25 pg/mL, with the upper end of the interquartile range for NRF-2 (41.03) and HO-1 (14.45) activation and restored redox balance (%DIS/NT: 26.31). No differences were observed between groups on the ECG. CONCLUSIONS: Colchicine suppresses inflammation, relieving inhibition of antioxidant defenses, enabling HBOT to fully activate NRF-2/HO-1. This synergistic HBOT + C strategy effectively mitigates MIRI, offering a promising multimodal therapy for remote organ protection after major ischemia.