Wrought nickel alloys are widely applied in hot static components for aero-engines, acquisition for the underlying mechanism of microstructural evolutions controlling mechanical degradation during elevated-temperature exposure is fundamentally vital to processing optimization as well as serving life prediction. In present work, the differential hot tensile characteristics during 500–2000 h exposure at 650 °C of wrought Inconel 718 alloy having specific microstructures designed via different processing routes were comparatively evaluated. The experimental results showed the static mechanical stability of Inconel 718 alloy was predominantly tailored by the complicated interaction of γ-matrix grain configuration and δ precipitation on grain boundaries (GBs). It mainly involved continuous GB-δ precipitation during the 500–2000 h exposure at 650 °C, which played opposite roles in homogeneous or heterogeneous grain configurations. GB-δ precipitation can improve hot ductility but deteriorate strength for homogeneous grain configuration, adequate GB-δ particles can improve the deformation compatibility between GBs and γ-matrix to achieve good balance between the strength and ductility as well as smaller mechanical fluctuations. The heterogeneous duplexing grain configuration exhibited enhanced mechanical sensitivity to sluggish GB-δ precipitation since the hot ductility was rapidly reduced by tiny δ particles with fracture mode transition. In comparison, appropriate sub-solvus solution prior to aging cycles can introduce GB-δ particles pre-existed in homogeneous grain configuration to benefit in superior long-term static mechanical stability for Inconel 718 alloy.