<p>Drought is a critical global environmental crisis that severely impacts wetlands, leading to ecosystem degradation. While numerous studies have explored various drought aspects, most focus on one or two key categories, neglecting a holistic approach that integrates all influencing factors. This study addresses this gap by developing a Comprehensive Drought Index (CDI) that combines climatic, agricultural, hydrological, and anthropogenic parameters. Utilizing satellite observations from 2000 to 2023 for the Anzali Wetland in Iran, we modeled drought’s multifaceted impacts through the computation of several drought indices, including the Standardized Precipitation Index (SPI), Palmer Drought Severity Index (PDSI), Soil Moisture Condition Index (SMCI), Temperature Condition Index (TCI), Vegetation Condition Index (VCI), Surface Water Supply Index (SWSI), Precipitation Condition Index (PCI), and Urban Thermal Field Variance Index (UTFVI). These indices were integrated into a comprehensive drought map using a weighted approach based on the correlation between SPI and the other indicators, with correlations exceeding 70%, underscoring the model’s accuracy. The resulting CDI provided a holistic drought assessment for the wetland. Results revealed 2019 as a wet year for the Anzali Wetland, while 2021 experienced a significant drought. Change detection analysis using Sentinel radar and optical data for 2019, 2021, and 2023 identified substantial human-induced land cover alterations, particularly in water areas. Between 2019 and 2021, 44% of water areas experienced human-made changes, which increased to 61% by 2023. A machine learning model trained with limited samples from 2019 achieved an overall accuracy of 92.92% and a Kappa coefficient of 87.16% and was subsequently applied to 2021 and 2023 data. The findings highlight severe drought conditions threatening the Anzali Wetland’s ecosystem, with human interference exacerbating the risk of total degradation.</p>