In the current work, the comprehensive combined effects of thermal aging, and three-dimensional (3D) in-plane and out-of-plane constraints on the fracture resistance curves (J-R) of reactor pressure vessel (RPV) steel, 16MND5 were investigated. First, the fracture experiments of RPV steel with different thermal aging durations using variously sized clamped single edge notched tension (SENT) specimens, were summarized. Then, 3D finite element method (FEM) was used to determine the constraint parameters for the tested specimens. From the analysis results, it was shown that the normalized T11, and the independent portion of T33 can accurately quantify the in-plane and out-of-plane constraint levels, respectively. Next, the in-plane and out-of-plane constraint-quantified R-curves were developed. Results showed that the effects of thermal aging, in-plane and out of-plane constraints on fracture toughness present significant interactions. The specific characteristics observed are: the influence of constraints on fracture toughness decreases with the increase of thermal aging duration, especially the in-plane constraint effect; the effect of thermal aging on fracture behavior is more significant under low constraint conditions. Further, the current in-plane and out-of-plane constraint dependent R-curves can easily reproduce all tested R-curves determined by clamped SENT specimens. It was also shown that they can accurately predict R-curves of pin-loaded SENT specimens or real RPV cracked structures under different thermal aging durations.