Background: South Korea faces a critical challenge with its rapidly declining fertility rates and an increasingly aging population, which significantly impacts the country's blood supply and demand. Despite these nationwide trends, regional disparities in blood supply and demand have not been thoroughly studied. Methods: This research utilized blood donation data from the Korean Red Cross and blood transfusion data from the Health Insurance Review and Assessment Service. We analyzed these datasets in conjunction with regional population projections to simulate blood supply and demand from 2021 to 2050 across South Korea. Sensitivity analyses were conducted to assess the impact of various factors, including the number of donors, age eligibility criteria for donations, frequency of donations, and blood discard rates. Results: Our projections indicate a decreasing trend in blood supply, from 2.6 million units in 2021 to 1.4 million units by 2050, while demand is expected to peak at 5.1 million units by 2045 before declining. Metropolitan areas, particularly Gyeonggi Province, are projected to experience the most severe shortages. Sensitivity analyses suggest that increasing the donation frequency of existing donors and relaxing age eligibility criteria are more effective strategies in addressing these imbalances than merely increasing the number of new donors. Blood discard rates showed minimal impact on the overall blood shortage. Conclusion The findings emphasize the urgent need for targeted strategies to mitigate national and regional blood supply shortages in South Korea. Encouraging frequent donations from experienced donors and broadening eligibility criteria are critical steps toward stabilizing the blood supply amidst demographic shifts. These strategies must be prioritized to address the impending regional disparities in blood availability.