Climate-induced heat stress poses a critical threat to cotton (Gossypium spp.) productivity, especially during the flowering and boll development stages. Elevated temperatures exceeding 35°C disrupt key physiological processes, impair photosynthesis, and alter hormonal homeostasis, ultimately triggering premature boll abscission. Central to this process is the formation of the abscission zone (AZ), driven by the upregulation of ethylene and abscisic acid (ABA) biosynthetic genes, which antagonize auxin transport and compromise cell wall integrity. This disruption results in reduced boll retention and significant yield losses under heat-stressed conditions. This review synthesizes current advances in understanding the molecular and physiological mechanisms underlying heat-induced boll shedding. We highlight the roles of heat shock proteins (HSPs), stress-responsive transcription factors, reactive oxygen species (ROS) signaling, and hormone crosstalk in AZ regulation. Furthermore, we explore integrative breeding approaches combining quantitative trait loci (QTL) mapping, transcriptomics, and CRISPR/Cas9-based gene editing to enhance thermotolerance in cotton. Agronomic interventions—including exogenous application of plant growth regulators and precision irrigation techniques—are also examined as complementary strategies for mitigating heat stress effects. Emerging technologies, such as nanotechnology-enabled delivery systems for stress modulators, offer promising avenues for targeted intervention. Finally, we propose a research framework centered on AZ-specific gene expression profiling, gene–hormone interaction networks, and translational breeding pipelines. These multidisciplinary insights form a robust foundation for the development of climate-resilient cotton cultivars suited to increasingly extreme agro-climatic conditions.