The present study was designed to evaluate the functional potential of common duckweed (Lemna minor L.) as a source of bioactive compounds of nutraceutical interest. The untargeted profiling of the bioactive components of common duckweed was carried out through ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS), in parallel with assessing in vitro antioxidant and enzymatic inhibition properties. The optimization of extraction parameters was determined using the response surface methodology (RSM) through a 3-factor central composite design. The process parameters included extraction temperature, % of ethanol, and ultrasound power, while the response variables were the phenolic content (considering each main phenolic class), total glucosinolates, total carotenoids, the antioxidant potential, and enzyme inhibition activities. The results revealed that common duckweed was a rich source of carotenoids and total flavonoids (mainly flavones and flavonols), followed by phenolic acids, low-molecular-weight phenolics, and glucosinolates. Interestingly, the total flavones, total flavonols and total carotenoid equivalents showed the highest and most positive correlation values with the bioactive properties measured. Finally, the combined RSM approach and unsupervised statistics allowed us to point out the pivotal impact of ethanol percentage in the extraction solvent to recover the highest amounts of bioactive compounds efficiently.