The importance of green chemistry has never been greater than it is today. With growing concerns about environmental sustainability, resource depletion, and the impact of chemical processes on human health and the ecosystem, the principles of green chemistry offer a crucial framework for addressing these challenges. This approach encompasses the entire analytical process, from sample preparation to instrumental analysis and waste management aiming to contribute to a more sustainable and eco-friendly analytical practice. The present work introduces a new spectrofluorimetric method characterized by high sensitivity for the quantification of midodrine hydrochloride, based on the amplification of midodrine’s intrinsic fluorescence (at λex 291 nm and λem 324 nm) through the addition of sodium dodecyl sulfate (SDS) above its critical micelle concentration, and Torell buffer (pH 6.0). The suggested approach was effectively validated according to ICH guidelines, and a statistical evaluation was conducted. The current method demonstrated high sensitivity, with linear range from 0.025 to 2.0 μg mL 1. The lower quantification and detection limit were 30 and 9.8 ng mL 1, in the respective order. It was efficiently employed to assess the drug concentration in its marketable tablet formulations, achieving exceptional recovery and without any disruptive impact from excipients. Additionally, this technique was employed to assess the uniformity of tablet contents in accordance with USP guidelines. Moreover, the whiteness profile using Red Green Blue algorithm and greenness profile using AGREE software were evaluated proving that the proposed technique demonstrates an outstanding level of environmental friendliness.