Development of reliable computational models to predict the high temperature deformation behavior of nickel-based superalloys is in the forefront of materials research. These alloys find wide applications in manufacturing of turbine blades and discs of aircraft engines. The microstructure of these alloys consists of the primary γ′-phase, and the secondary and tertiary precipitates (of Ni3Al type) are dispersed as γ′-phases in the gamma matrix. It is computationally expensive to incorporate the explicit finite element model of the γ-γ′ microstructure in a crystal plasticity-based constitutive framework to simulate the response of the polycrystalline microstructure. Existing models in literature do not account for these underlying micro-structural features which are important for simulation of polycrystalline response. The aim of this work is to develop a physically motivated multi-scale approach for simulation of high temperature response of nickel-based superalloys. At the lower length scale, a dislocation density-based crystal plasticity model is developed which simulates the response of various types of microstructures. The microstructures are designed with various shapes and volume fractions of γ′-precipitates. A new model for simulation of the mechanism of anti-phase boundary shearing of the γ′-precipitates, by the matrix dislocations, is developed in this work. The lower scale model is homogenized as a function of various micro-structural parameters, and the homogenized model is used in the next scale of multi-scale simulation. In addition, a new criterion for initiation of micro-twin and a constitutive model for twin strain accumulation are developed. This new micro-twin model along with the homogenized crystal plasticity model has been used to simulate the creep response of a single crystal nickel-based superalloy, and the results have been compared with those of experiment from literature. It was observed that the new model has been able to model the tension–compression asymmetry as observed in single crystal experiments.