The rapid development of data centers (DCs) has led to a marked increase in energy consumption in recent years, which poses a direct challenge to global efforts aimed at reducing carbon emissions. In regions with hot and humid climates, the energy demand is largely driven by air conditioning systems necessarily to maintain appropriate operational temperatures. This study proposes a novel multi-stage indirect evaporative cooling (IEC) system, incorporating a liquid desiccant in the primary air channel to address the cooling demands of such DCs. Our approach involves a two-stage process where the first stage uses a liquid desiccant-based IEC (LD-IEC) for air dehumidification and the second stage utilizes the treated air from the first stage as the secondary air to enhance the cooling effect. A simulation model of the proposed system is established with validation, and the performance of the multi-stage system was also discussed based on different operation modes. Furthermore, a case study was conducted to investigate the feasibility of using this system in the DC under a typical hot and humid zone. The findings reveal that the first-stage LD-IEC is capable of diminishing the wet-bulb temperature of the ambient air. Furthermore, the case study demonstrates that the proposed system can greatly improve the temperature drop by 72.7% compared to the single IEC, which noticeably reduces the operation time of energy-intensive supplementary cooling equipment from 5092 h to 31 h given the supply air temperature threshold of 25 °C. In summary, the proposed system could substantially decrease reliance on traditional cooling systems, which demonstrates a promising avenue to fully use this passive cooling technology for cooling DCs.