© 2021 by the authors. Licensee MDPI, Basel, Switzerland.In this research, the mechanical properties of lightweight mortars containing different percentages of additional powder materials has been investigated using response surface methodology (RSM). Box–Behnken design, one of the RSM techniques, was used to study the effects of silica fume content (5, 10, and 15%), vermiculite/cement (V/C) ratio (4, 6, and 8), and temperature (300, 600, and 900◦C) on the ultrasonic pulse velocity (UPV), bending strength, and compressive strength of lightweight mortars. Design expert statistical software was accustomed to determining and evaluating the mix-design of materials in mortar mixtures and temperature effect on mortars. After preliminary experimental research of the relationships between independent and response variables, regression models were built. During the selection of the model parameters, F value, p-value, and R2 values of the statistical models were taken into account by using the backward elimination technique. The results showed a high correlation between the variables and responses. Multi-objective optimization results showed that the critical temperatures for different levels of silica fume (5–10–15%) were obtained as 371.6◦C, 306.3◦C, and 436◦C, respectively, when the V/C ratio kept constant as 4. According to the results obtained at high desirability levels, it is found that the UPS values varied in the range of 2480–2737 m/s, flexural strength of 3.13–3.81 MPa, and compressive strength of 9.9–11.5 MPa at these critical temperatures. As a result of this research, RSM is highly recommended to evaluate mechanical properties where concrete includes some additional powder materials and was exposed to high temperature.