Although synthetic bioactive compounds are approved in many countries for food applications, they are becoming less and less welcome by consumers. Therefore, there has been an increasing interest in replacing these synthetic compounds by natural bioactive compounds. These natural compounds can be used as food additives to maintain the food quality, food safety and appeal, and as food supplements or nutraceuticals to correct nutritional deficiencies, maintain a suitable intake of nutrients, or to support physiological functions, respectively. Recent studies reveal that numerous food wastes, particularly fruit and vegetables byproducts, are a good source of bioactive compounds that can be extracted and reintroduced into the food chain as natural food additives or in food matrices for obtaining nutraceuticals and functional foods. This review addresses general questions concerning the use of fruit and vegetables byproducts as new sources of natural bioactive compounds that are being addressed to foods as natural additives and supplements. Those bioactive compounds must follow the legal requirements and evaluations to assess the risks for human health and their toxicity must be considered before being launched into the market. To overcome the potential health risk while increasing the biological activity, stability and biodistribution of the supplements’ technological alternatives have been studied such as encapsulation of bioactive compounds into micro or nanoparticles or nanoemulsions. This will allow enhancing the stability and release along the gastrointestinal tract in a controlled manner into the specific tissues. This review summarizes the valorization path that a bioactive compound recovered from an agro-food waste can face from the moment their potentialities are exhibited until it reaches the final consumer and the safety and toxicity challenges, they may overcome.