Alkali stress, marked by high soil pH (>8.5) and excess sodium bicarbonate/carbonate, threatens global cotton productivity, especially in arid regions. This review aims to synthesize the unique physiological constraints of high-pH stress distinct from neutral salinity and evaluates the novelty of recent integrated agronomic and biotechnological interventions. Various soil factors such as clay content, cation exchange, poor irrigation practices (saline water, drainage issues), and human activities (over-fertilization, pollution), disrupts ion balance, induce osmotic stress, and damages of cellular structures. Main findings highlight that alkali stress imposes specific non-stomatal photosynthetic limitations and root architectural damage via H+-ATPase inhibition, impairing germination, root growth, nutrient uptake, and photosynthesis leading to stunted plants, chlorosis, and reduced boll yield with inferior fiber quality. Various approaches have been identified to alleviate this type of toxicity. For example, molecular adaptations include stress-responsive genes (GhSOS1, GhNHX1, GhADT5) regulating ion transport and antioxidant pathways. Finally, practical applications are proposed through a sustainable management framework: Mechanical approaches like soil amendments (gypsum, mulching), precision irrigation, CRISPR-edited cultivars (AlHAK1, GhERF2), and microbial symbionts (PGPR, AM fungi) will be valuable for cotton growth and production. Utilizing a multidisciplinary approach, coupled with agronomic, biochemical, and genetic techniques, is the best way to enhance resilience, while addressing knowledge gaps with respect to soil alkalinity and climate stressors.