Optimal and cost-effective energy efficiency design and operation options are evaluated for office buildings in Tunisia. In the analysis, several design and operation features are considered including orientation, window location and size, high performance glazing types, wall and roof insulation levels, energy efficient lighting systems, daylighting controls, temperature settings, and energy efficient heating and cooling systems. First, the results of the optimization results from a sequential search technique are compared against those obtained by a more time consuming brute-force optimization approach. Then, the optimal design features for a prototypical office building are determined for selected locations in Tunisia. The optimization results indicate that utilizing daylighting controls, energy efficient lighting fixtures, and low-e double glazing, and roof insulation are required energy efficiency measures to design high energy performance office buildings throughout climatic zones in Tunisia. In particular, it is found that implementing these measures can cost-effectively reduce the annual energy use by 50% compared to the current design practices of office buildings in Tunisia.