Excess health and safety risks of commercial drivers are largely determined by, embedded in, or operate as complex, dynamic, and randomly determined systems with interacting parts. Yet, prevailing epidemiology is entrenched in narrow, deterministic, and static exposure‐response frameworks along with ensuing inadequate data and limiting methods, thereby perpetuating an incomplete understanding of commercial drivers' health and safety risks. This paper is grounded in our ongoing research that conceptualizes health and safety challenges of working people as multilayered “wholes” of interacting work and nonwork factors, exemplified by complex‐systems epistemologies. Building upon and expanding these assumptions, herein we: (a) discuss how insights from integrative exposome and network‐science‐based frameworks can enhance our understanding of commercial drivers' chronic disease and injury burden; (b) introduce the “working life exposome of commercial driving” (WLE‐CD)—an array of multifactorial and interdependent work and nonwork exposures and associated biological responses that concurrently or sequentially impact commercial drivers' health and safety during and beyond their work tenure; (c) conceptualize commercial drivers' health and safety risks as multilayered networks centered on the WLE‐CD and network relational patterns and topological properties—that is, arrangement, connections, and relationships among network components—that largely govern risk dynamics; and (d) elucidate how integrative exposome and network‐science‐based innovations can contribute to a more comprehensive understanding of commercial drivers' chronic disease and injury risk dynamics. Development, validation, and proliferation of this emerging discourse can move commercial driving epidemiology to the frontier of science with implications for policy, action, other working populations, and population health at large.