During Cambrian Stage 4 (~514 Ma) the oceans were widely populated with endemic trilobites and three major faunas can be distinguished: olenellids, redlichiids, and paradoxidids. The lower-middle Cambrian boundary in Laurentia was based on the first major trilobite extinction event that is known as the Olenellid Biomere boundary. However, international correlation across this boundary (the Cambrian Series 2-Series 3 boundary) has been a challenge since the formal proposal of a four-series subdivision of the Cambrian System in 2005. Recently, the base of the international Cambrian Series 3 and of Stage 5 has been named as the base of the Miaolingian Series and Wuliuan Stage. This study provides detailed chemostratigraphy coupled with biostratigraphy and sequence stratigraphy across this critical boundary interval based on eight sections in North America and South China. Our results show robust isotopic evidence associated with major faunal turnovers across the Cambrian Series 2-Series 3 boundary in both Laurentia and South China. While the olenellid extinction event in Laurentia and the gradual extinction of redlichiids in South China are linked by an abrupt negative carbonate carbon excursion, the first appearance datum of Oryctocephalus indicus is currently the best horizon to achieve correlation between the two regions.