<p>Pre-emergence herbicides are widely used to control weeds in soybean systems, although concerns remain regarding their potential to induce phytotoxicity and reduce crop performance. This study evaluated the effects of pre-emergence herbicides and the use of a natural safener based on <i>Ascophyllum nodosum</i> on soybean under field conditions. Field trials were conducted over three growing seasons (2022/2023, 2023/2024, and 2024/2025) in São Desidério, Bahia, Brazil, using a factorial arrangement in a randomized complete block design with four replications. Treatments included ten herbicides applied alone or combined with a seed-applied safener (1.5 mL kg^-1), across eleven soybean cultivars. Agronomic, physiological, and spectral variables were evaluated. Data were analyzed using ANOVA (5%), with Tukey’s test for mean comparison, and non-parametric tests when assumptions were not met. Soybean yield increased across seasons, and the safener significantly improved yield, plant population, and plant height in the first two seasons, although no effect was observed in the third season. Herbicide effects varied by molecule and cultivar, confirming strong genotype × herbicide interactions. No consistent yield penalties or evidence of “hidden phytotoxicity” were observed. Early phytotoxicity was transient and did not affect final productivity. The safener slightly increased early phytotoxicity but enhanced NDVI (~4%), suggesting improved canopy development and recovery. No significant effects were detected on physiological parameters. These results indicate that pre-emergence herbicides are selective and safe under proper management, while the natural safener enhances early crop performance through indirect physiological benefits rather than direct protection against injury, supporting its use as a complementary strategy to improve crop resilience.</p>