The main species and chemical processes in low‐temperature atmospheric‐pressure He + O2 plasmas are identified using a comprehensive global model. The simulation results highlight the significance of Penning processes at low oxygen concentration, and the increasingly important role of electron attachment as the oxygen concentration increases. With increasing the oxygen concentration, the electron energy dissipation shifts from elastic collisions with He to dissociative excitation and attachment of O2 molecules, and large ions (${\rm O}_{3}^{ + } $, ${\rm O}_{4}^{ + } $) become the dominant charged species. Generation and loss of ROS (O, O(1D), O(1S), O2(a1Δg), O2(b1∑ g+), O3) relevant for biomedical applications are discussed.