An urgent global challenge for the construction industry is the reduction of greenhouse gases emissions. Therefore, the industry must transition towards the adoption of more sustainable construction practices, including the use of eco-efficient materials, to achieve net-zero emissions targets. One strategy for reducing the environmental impact of construction is using less Portland cement (PC) in concrete. This can be achieved by adopting new hybrid alkali-activated cements (HACs) produced with low PC clinker contents (30–50 wt.%) blended with supplementary cementitious materials (SCMs) such as fly ash or blast furnace slag and activators. In recent years, the interest in using calcined clays have increased significantly, as these materials are potentially available in many regions worldwide and can help meet the growing demand for sustainable construction materials. However, commercially available sources remain limited, and large-scale applications are still emerging. Hence, studies evaluating the potential for producing HACs using different clay resources are very limited. This paper analysed the potential of mixed clays as SCMs, focusing on enhancing their pozzolanic reactivity through thermal (TA) and/or mechanochemical (MCA) activation processes, and presents a brief overview of the main techniques used to assess structural and mineralogical transformation in activated clays. The review also highlights and discusses the application of optimised activated clays in HACs systems incorporating PC, varying clay contents (50–70%), when using as alkali activator sodium sulphate (Na2SO4).