Repercussion to the rapid increase in population annually and the decline in agricultural fruits and vegetables productivity, we are facing a real danger, especially with the population expected to reach 9.6 billion people by 2050. Fruits are a specialty as one of the most consumed agricultural products due to their richness in fiber, nutrients, salts, vitamins, and antioxidants. Unfortunately, fruits have a short shelf life and rot quickly due to their high percentage of moisture content 75–95%. Postharvest diseases of fruits cause more than 30% loss as the consumer chooses it based on quality, color, texture, lack of decay, and smell. To control post-harvest disease, widespread uncontrolled use of chemical pesticides, insecticides, fungicides, and bactericides before and after harvest has led to the development of diseases with resistant strains and decreased the efficacy of these pesticides. Also, the uses of these toxic chemicals have environmental damage effects and health issues. Recently, nanotechnology has emphasized its role in managing post-harvest disease, especially as an antimicrobial efficient agent, particularly in food processing, storage, and product transportation. Nano-sensors, nanocoating, nano-bubbles, and nano-packing are all efficient figures of nanomaterials in food processing. In this chapter, we will shed light on the strategies of post-harvest disease management, nanotechnology techiest in fruit preservation, and applications of nanotechnology to reduce post-harvest losses on fruit crops, such as citrus fruits, grapes, bananas, mangos, peaches, guava, and others.