<p>This paper investigates the optimization of stiffness distribution in semi-rigid joints within both the plan and height dimensions of steel space frames. To achieve this, advanced structural analysis and optimization techniques, specifically the Practical Advanced Analysis (PAA) method and the Slime Mould Algorithm (SMA), are employed. The PAA method are utilized to effectively capture material inelasticity and second-order structural effects. The structural model incorporates a zero-length element consisting of three rotational springs and three translational springs, with rotational spring stiffness values derived from the Kishi-Chen Power Model. This model is instrumental in predicting the nonlinearity exhibited by semi-rigid connections. SMA, a global optimization algorithm, is then applied to determine the optimal solution. This method has performed very well in optimization problems; therefore, it is being utilized for the first time in this type of problem. In this study, the optimization variables extend beyond the cross-sectional properties of beam and column members to include various types of semi-rigid connections. The results, obtained from analyzing two distinct three-dimensional steel frames—a four-story and an eight-story structure—reveal that connection stiffness is distributed more prominently within the structure’s inside plane compared to its edges and corners. Furthermore, the distribution of joint stiffness within the structure’s height either remains constant or increases. Additionally, a reverse relationship is observed between joint stiffness and column stiffness.</p>