In many regions of the world, the growth in water demand has had a greater impact on water resources than climate change. This study aims to provide a better understanding of the climatic (meteorological drought) and human (e.g., human extraction) effects on groundwater stress and sustainability at a local scale (Goharkooh Plain aquifer). The study area is a small part of the Lut Desert catchment, the driest basin in Iran. Climate fluctuations and uncontrolled human activities in recent decades have led to the degradation of the terrestrial environment in this watershed. To achieve the research objectives, groundwater fluctuations were examined using groundwater level data from 39 piezometers with the SWI index, and climate fluctuations were examined using the SPEI index over the 2002–2018 period. The relationship between groundwater fluctuations and climate variability was investigated using correlation coefficients and regression relationships. The results showed that the groundwater level in the Goharkuh Plain aquifer declined during the study period. Groundwater fluctuations were significantly correlated with drought indices. Meteorological droughts explained 55% of the groundwater fluctuations in the Goharkooh Plain aquifer, while 45% were due to other factors, among which the role of human activities is prominent. Among human activities, the excessive increase in groundwater extraction and its allocation to agriculture using unsustainable agricultural methods have significantly contributed to the unstable condition of groundwater resources in the Goharkooh aquifer. Therefore, intervention measures are necessary to prevent the exacerbation of the aquifer's condition and to improve it. The most important and essential intervention measures include natural and artificial recharge of the aquifer, along with smart control of groundwater discharge, and subsequently, changing agricultural practices and smart water allocation.