Hyperthermia, the heating of cancerous tumors can improve the efficiency of cancer treatment when added as an adjuvant to Radio therapy and Chemotherapy. Main goal of this work is to design a periodic output feedback controller to control the power of ultrasound transducer so that uniform temperature distribution is maintained in the targeted tissues all through the hyperthermia treatment process. For this purpose first a tumor layer surrounded by muscle layer is modeled using Penne’s bio heat transfer equation and a higher order state space model to the bio heat transfer problem is obtained by finite difference method. In second step an experimental proto type for the above model is created using agar phantom which mimics the human tissue. Temperature response of the simulated model is compared with the experimental outcome to demonstrate the validity of simulated model. Now a periodic output feedback controller is designed for the simulated hyperthermia model. The performance of the controller is evaluated by framing a desired trajectory which meets the treatment goals of hyperthermia. Closed loop error norm and the open loop error norm are evaluated to prove the efficiency of the designed controller. Simulations are also done to show the robustness of the controller in spite of variation in blood perfusion. Simulations proved that hyperthermia system is robust to blood perfusion variation and the closed loop norm has improved more than 40% compared to open loop norm in certain perfusion cases.