Organic fluorophores with near-infrared (NIR) emission and reduced molecular weight are crucial for advancing bioimaging and biosensing technologies. Traditional methods, such as conjugation expansion and heteroatom engineering, often fail to reduce fluorophore size without sacrificing NIR emission properties. Addressing this challenge, our study utilized quantum chemical calculations and structure-property relationship analysis to establish an iterative design approach and enable precision engineering for compact, single-benzene-based NIR fluorophores. These newly developed fluorophores exhibit emissions above 700 nm and maintain molecular weights under 200 g/mol, approximately 50% of that of Cy7. Additionally, they display unique environmental sensitivity—non-emissive in aqueous solutions but highly emissive in lipid environments. This property significantly enhances their utility in wash-free imaging of live cells. Our findings mark a substantial breakthrough in fluorophore engineering, paving the way for more efficient and adaptable imaging methodologies.