The observing system design of multidisciplinary field measurements involves a variety of considerations on logistics, safety, and science objectives. Typically, this is done based on investigator intuition and designs of prior field measurements. However, there is potential for considerable increases in efficiency, safety, and scientific success by integrating numerical simulations in the design process. Here, we present a novel numerical simulation–environmental response function (NS–ERF) approach to observing system simulation experiments that aids surface–atmosphere synthesis at the interface of mesoscale and microscale meteorology. In a case study we demonstrate application of the NS–ERF approach to optimize the Chequamegon Heterogeneous Ecosystem Energy-balance Study Enabled by a High-density Extensive Array of Detectors 2019 (CHEESEHEAD19). During CHEESEHEAD19 pre-field simulation experiments, we considered the placement of 20 eddy covariance flux towers, operations for 72 h of low-altitude flux aircraft measurements, and integration of various remote sensing data products. A 2 h high-resolution large eddy simulation created a cloud-free virtual atmosphere for surface and meteorological conditions characteristic of the field campaign domain and period. To explore two specific design hypotheses we super-sampled this virtual atmosphere as observed by 13 different yet simultaneous observing system designs consisting of virtual ground, airborne, and satellite observations. We then analyzed these virtual observations through ERFs to yield an optimal aircraft flight strategy for augmenting a stratified random flux tower network in combination with satellite retrievals. We demonstrate how the novel NS–ERF approach doubled CHEESEHEAD19's potential to explore energy balance closure and spatial patterning science objectives while substantially simplifying logistics. Owing to its modular extensibility, NS–ERF lends itself to optimizing observing system designs also for natural climate solutions, emission inventory validation, urban air quality, industry leak detection, and multi-species applications, among other use cases.