Within the framework of the EUROfusion research activities on the DEMO Water-Cooled Lithium Lead (WCLL) Breeding Blanket (BB) design, a research study was performed to preliminarily optimize, from the thermal point of view, the WCLL Central Outboard Blanket (COB) segment in order to investigate its structural behaviour under a realistic thermal field. In particular, a study of thermal analyses was performed to optimize the Double Walled Tubes and Segment Box cooling channels’ geometric configurations along the poloidal extension of the WCLL COB segment, in order to obtain a spatial temperature distribution fulfilling the thermal design requirement. Then, the thermo-mechanical analysis of the WCLL COB segment under Normal Operation (NO, representing nominal conditions), Upper Vertical Displacements Event (UVDE, representing a plasma disruption event) and Over-Pressurization (OP, representing an in-box loss of coolant accident) scenarios were carried out, assuming the previously obtained thermal field, to realistically predict displacement and stress fields. Finally, a stress linearization procedure allowed comparing the stress values obtained in some critical regions of the structure with the criteria prescribed by the reference design standard RCC-MRx. A theoretical–numerical approach based on the Finite Element Method (FEM) was followed using the commercial code Abaqus v. 6.14.