Flexibility is an important feature of organic thin-film transistor (OTFT) technology. The need for flexibility adds challenges to the mechanical reliability of the OTFTs. This work focuses on mechanical and thermal failure mechanisms in an OTFT and their relation with the substrate properties. It is observed that four material parameters of the substrate, namely, Young’s modulus, thermal conductivity, coefficient of thermal expansion, and glass transition temperature, are crucial in determining the reliability and flexibility of the OTFT. Further more, using an interval-based technique for order preference by similarity to ideal solution (TOPSIS) technique, five polymer substrates including polycarbonate (PC), polyethylene naphthalate (PEN), polyethylene terephthalate (PET), polyimide (PI), and polyethersulfone (PES) are analyzed. It is concluded that PI is the most suitable substrate material for OTFTs to improve flexibility and reliability.