The disposal of waste vehicle tires is an environmental and health problem, as their recycling is very difficult. One of the effective ways of recycling is using these tires as partial replacement of Portland cement in construction industry. In this study, a systematic experimental study (by making 810 laboratory samples) is performed on concrete made with finely ground rubber (GR) and metakaolin (MK) as partial replacements of cement to investigate the compressive strength, splitting tensile strength, flexural strength, water absorption, and dry unit weight. The main goal of this study is to achieve the optimal proportions of concrete incorporating GR and MK by maximizing mechanical strengths while minimizing the water absorption (WA) of concrete. To do so, 7 concrete mixtures containing GR are produced with 3 different cement contents: 350, 400, and 450 kg/m3 in conjunction with 2 different water-cement ratios: 0.45 and 0.50. Also, 1 concrete mix is used to optimize the concrete with hybrid blends of GR and MK by employing the response surface methodology (RSM). GR and MK are applied as partial replacements of Portland cement in ranges of 0–30 vol% and 0–20 vol%, respectively. The results show that the use of GR and MK in concrete has a significant effect on its mechanical and durability properties and, thus, reduces the cement consumption which can contribute to decreasing the negative impacts of cement production on the environment. According to the optimization results, 4.2% and 19.5 vol% replacements of cement with GR and MK, respectively, can be considered as the optimum mixture compositions of hybrid concrete to maximize compressive and splitting tensile strengths by about 1–4% and 6–8%, respectively, while minimizing WA by about 48%. Depending on the flexural strength results, the amounts are changed into 1.8% and 14.7% while the flexural strength increases by about 11%.