Fluorescein-based chemosensors have garnered significant attention for their remarkable ability to detect hazardous ions, particularly copper ions (Cu2+), due to their excellent photophysical properties, high fluorescence intensity, and structural adaptability. This review explores recent advancements in the design and synthesis of fluorescein derivatives, emphasizing their functional modifications at the xanthene and benzene moieties. These modifications enable precise selectivity and sensitivity through mechanisms such as fluorescence resonance energy transfer (FRET), chelation-enhanced fluorescence (CHEF), photo-induced electron transfer (PET) fluorescence resonance energy transfer (FRET), Aggregation induced emission (AIE). Fluorescein chemosensors are extensively applied in environmental monitoring, biological imaging, and industrial analysis due to their high efficiency and versatility. Particular emphasis is placed on their application in detecting Cu²⁺, a critical ion due to its dual role as an essential micronutrient and an environmental toxin. Mechanistic insights into fluorescence modulation and structure-function relationships are discussed to highlight their efficacy in real-world scenarios. Despite their promise, challenges such as reliance on organic solvents and reduced stability in extreme conditions remain. Future research should focus on creating water-compatible, non-toxic probes with improved stability and expanding their application to other analytes. Such advancements will enhance their utility in addressing environmental and biological challenges while ensuring safer, sustainable solutions.