This paper designs a novel least squares (LS) meshless method for the three-dimensional (3D) problem of multi-component high-speed non-equilibrium reaction jet. Specifically, the space derivative was solved by the LS method, and the artificially upstream flux vector splitting (AUFS) scheme was introduced to compute the convection term in the control equation. Considering the possibility of chemical reactions, the flow field parameters were updated by the finite-rate reaction model; the rigidity of chemical reactions was solved by the time splitting method. In addition, the 3D computational domain was discretized into simple weighted points with clear physical meanings. On this basis, the complex problems of the steady flow around the high-speed flying projectile with the angle of attack, and the 3D muzzle flow field with brake were calculated. The results prove that the proposed LS meshless method is a feasible way to capture the shock structure in complex flow fields. The proposed method provides a new solution to multi-component high-speed non-equilibrium reaction jets.