One of the important components of a nuclear fuel cycle facility is a hot cell. Hot cells are engineered robust structures and barriers, which are used to handle radioactive materials and to keep workers, public, and the environment safe from radioactive materials. To provide a confinement function for these hot cells, it is necessary to maintain the soundness of the physical structure, but also to maintain the negative pressure inside the hot cell using the operation of the heating, ventilation, and air conditioning (HVAC) systems. The negative pressure inside the hot cells allows air to enter from outside hot cells and limits the leakage of any contaminant or radioactive material within the hot cell to the outside. Thus, the HVAC system is one of the major components for maintaining this negative pressure in the hot cell. However, as the facility ages, all the components of the hot cell HVAC system are also subject to age-related deterioration, which can cause an unexpected failure of some parts. The abnormal operating condition from the failure results in the increase of facility downtime and the decrease in operating efficiency. Although some major parts are considered and constructed in redundancy and diversity aspects, an unexpected failure and abnormal operating condition could result in reduction of public acceptance and reliability to the facility. With the advent of the 4th Industrial Revolution, prognostics and health management (PHM) technology is advancing at a rapid pace. Korea Hydro & Nuclear Power, Siemens, and other companies have already developed technologies to constantly monitor the integrity of power plants and are applying the technology in the form of digital twins for efficiency and safety of their facility operation. The main point of PHM, based on this study, is to monitor changes and variations of soundness and safety of the operation and equipment to analyze current conditions and to ultimately predict the precursors of unexpected failures in advance. Through PHM, it would be possible to establish a maintenance plan before the failure occurs and to perform predictive maintenance rather than corrective maintenance after failures of any component. Therefore, it is of importance to select appropriate diagnostic techniques to monitor and to diagnose the condition of major components using the constant examination and investigation of the PHM technology. In this study, diagnostic techniques are investigated for monitoring of HVAC and discussed for application of PHM into nuclear fuel cycle facilities with hot cells.