High-efficient pesticide application equipment for protected cultivation is scarce. In response, a fixed-pipe twin-fluid clod fogger (FTCF) was proposed as a potential solution. To investigate the optimal nozzle layout and spray performance, a computational fluid dynamics (CFD) model was used to study the airflow distribution and spray deposition of a FTCF with different nozzle settings using the Euler-Lagrange approach. Specifically, two piping configurations, middle-cross-inverted (MCI) and bilateral-malposed-opposite (BMO), were combined with three nozzle spacings (2 m, 3 m, 4 m) resulting in six nozzle settings. Additionally, a greenhouse spray trial was conducted to test the performance of FTCF with the selected nozzle settings and to validate the model. The simulation results revealed that MCI piping configuration exhibited a stronger airflow disturbance compared to BMO configuration, indicating a more significant air-guided effect in the MCI configuration. Combining this finding with the ground droplet distribution analysis of MCI piping configuration, it was observed that MCI-2 m had the lowest coefficient of variation (CV) for ground deposition (20.56%). Consequently, MCI-2 m was determined as the most optimal nozzle setting. Verification results demonstrated a high consistency between experimental and simulated spray deposition results. The FTCF system effectively generated a three-dimensional airflow field throughout the greenhouse environment. Furthermore, jet flow produced by FTCF disrupted the overall airflow pattern within the greenhouse space which facilitated droplet suspension and dispersion. This study provides valuable insights and innovative ideas for enhancing pesticide application technologies in protected cultivations. © 2024 Society of Chemical Industry.