Traffic control is very important for two-lane highway lane-closure work zone traffic management. Control of the open lane’s right of way is very similar to that of a two-phase signalized intersection. Thus, four control strategies including flagger control, pre-timed control proposed by Schonfeld, pre-timed control proposed by Webster, and actuated control are employed for possible use at work zones. Two primary methodologies, the mathematical delay model adopted from signalized intersections, and the simulation model calibrated with field data, are proposed. The simulation and mathematical results show that control strategies for two one-way road intersections could be used for two-lane highway lane-closure work zones. Flagger control after gap-out distance optimization prevails over all the other control strategies in terms of stopped delay, queue length, and throughput, under low or high volumes. Actuated control could be a good alternative for work zone areas due to its small queue length and large vehicle throughput under moderate volume conditions. Our findings may help to optimize the work-zone control strategy and improve operational efficiency at two-lane highway lane-closure work zones.