A novel highly constrained optimal gliding guidance algorithm, which can satisfy multiple path and terminal constraints in the presence of no-fly zones for hypersonic vehicle, is investigated in this paper. It employs line-of-sight angle to describe the relative location relationship between flight path and no-fly zones, and proposes boundaries selection algorithm for each no-fly zone, which is called avoidance strategy, with minimum energy consumption. The boundaries determined by avoidance strategy divide the flight process and guidance task into several stages. In each stage, it constructs guidance models based on quasi-equilibrium glide condition in longitudinal and lateral directions respectively, and employs optimal control to generate guidance law to satisfy terminal location, altitude, and flight path angle constraints. In addition, all the path constraints, including heating rate, dynamic pressure, and overload, are converted into the angle-of-attack constraint to ensure the guidance mission can be accomplished successfully. This algorithm is independent of standard trajectory, and all the guidance commands, including the bank angle and the angle of attack, can be calculated analytically in real time and adaptively. Finally, the simulation results of CAV-H indicate that the proposed strategy can guide the vehicle to satisfy multiple different constraints with high precision and avoid no-fly zones effectively.