Wheat represents one of the most widely consumed cereals worldwide. Cultivated in winter and spring, it is vulnerable to an array of different pathogens, including fungi, which are managed largely through the in-field application of fungicides. During this study, a 4-year field investigation (2018–2021) was performed in France, aiming to assess the efficacy of fungicide treatment to reduce mycotoxin contamination in common and durum wheat. Several different commercially available fungicides were applied via sprayers. Concentrations of mycotoxins and fungal metabolites in wheat were determined using a multi-analyte liquid-chromatography–tandem-mass-spectrometry-based method. The highest contamination levels and strongest effects of fungicides were observed in 2018, followed by 2021. A significant fungicide-mediated reduction was observed for the trichothecenes deoxynivalenol, deoxynivalenol-3-glucoside, nivalenol, and nivalenol-3-glucoside. Furthermore, fungicide treatment also reduced levels of culmorin and its hydroxy metabolites 5- and 15-hydroxy-culmorin, as well as aurofusarin. Interestingly, the Alternaria metabolite infectopyron was increased following fungicide treatment. In conclusion, fungicide treatment was effective in reducing mycotoxin levels in wheat. However, as complete prevention of mycotoxin contamination was not achieved, fungicide treatment should always be combined with other pre- and post-harvest mycotoxin mitigation strategies to improve food and feed safety.