Besides large-scale space missions, the spread of CubeSats for a variety of applications is increasingly requiring the development of systematic approaches for risk management. Being these applications are based on components with low TRL (Technology Readiness Level) or with limited performance data, it is required to define approaches which ensure a systematic perspective. This paper aims to present a reliability engineering approach based on FMECA (Failure Mode, Effects, and Criticality Analysis) to manage CubeSat reliability data and prioritize criticalities early in the design phase. The approach firstly proposes an alpha-numeric coding system to support the identification and labeling of failure modes for typical CubeSats’ items. Subsequently, each FMECA coefficient (i.e., Severity, Occurrence, Detectability) has been linked to the CubeSat’s structural properties, reducing subjectivity by means of techno-centric proxy indicators. The approach has been validated in the design phases of a 6-Units university CubeSat for the observation of M-Dwarf stars and binary systems. The performed analysis supported the design process and allowed to identify the major criticalities of the CubeSat design, as demonstrated in the extended case study included in the paper. The formalized method could be applied to design procedures for nano-satellites, as well as being expanded for research and development in a variety of space missions.