To address the issue of high CO2 emissions from global cement production, the use of waste materials, like waste clays, is becoming increasingly popular. This study focuses on natural mixed-layer waste clays from Australia as supplementary cementitious materials (SCMs) in concrete, exploring the challenges posed by varying mineral compositions and activation methods. Three types of waste clays with different mineralogical compositions and sources were examined, with activation techniques including calcination and mechanical grinding, adjustment of temperature (for calcination), and duration (for mechanical activation) of activation. The results pinpoint the best conditions for improving clay reactivity. It was also discovered that calcined clays with more than 20% total clay mineral content and a particle fineness exceeding 85% exhibited superior mechanical performance compared to control mixes that did not include clays.