Waveguide Termination

I have an issue in designing a Waveguide port termination. The waveguide simulation works for the desired frequency when both the ends of the waveguide are driven by a waveguide port. When single ended simulation happens the S11 performance is poor.

Need more information. What is termination type, what software?

When using two identical ports if waveguide length is multiple of 180deg, then you may obtain good S11/S21 even in unmatched configuration, because impedance repeats each 180 deg. I often perform two simulations for microstrip/waveguide structures: first - original design, second - original design with additional 90deg line/extended waveguide length. If something is unmatched this 90 degree reveal it by doing transform.

HFSS.

The issue is not the waveguide. The standard waveguide simulation gives optimum S11 and S12/S21 performance. The problem starts when the waveguide is used as a single ended i.e, waveguide antenna. The S11 degrades in this configuration.

Sounds fair, you'll need an impedance matching transition, e.g. a horn to make a suitable antenna. The issue is your expectation of matching the waveguide to free space without a transition.