Highway Work Zones (HWZs) are associated with significant adverse impacts on safety, mobility, and work costs. The objective of this paper is two-fold: First, to quantify the impacts of HWZs on safety, mobility, and work costs. Second, to develop an optimization model to minimize the total costs associated with HWZs by controlling site geometry, Temporary Traffic Control (TTC), and work management. This model implements a location-based schedule within the cost evaluation. A genetic algorithm is used to determine a set of optimal scheduling and decision variables. The performance of the model is demonstrated in a case study. The results reveal that crash costs, which were often ignored or only included indirectly in previous works, are a substantial cost component. Their explicit inclusion in the optimization process significantly affects the total cost and the optimal operations of the HWZ. Furthermore, the inclusion of a location-based schedule in the model is instrumental and affects the optimal solution since all HWZ cost components are affected by the work processes and project duration. Moreover, consideration of the effects of TTC on the optimized function has a substantial influence on the total cost. The model can support transportation agencies and local authorities in mitigating the adverse impacts associated with HWZs.