The combined application of selenium (Se) and diverse plant growth regulators, particularly under drought stress, represents a crucial strategy for augmenting secondary metabolite synthesis in medicinal plants. This study conducted using a split-split-plot factorial design was used within a randomized complete block design containing three replications in diverse climatic regions such as Varamin, Firuzabad, and Gorgan. This study aims to assess irrigation treatments (90 ± 5% and 25 ± 5% field capacity) as main plots and foliar applications involving Se and plant growth regulators (Strigolactone: SLs and Forchlorfenuron: CPPU) as well as various Stevia genotypes (Indian and Chinese) were incorporated as subplots. Severe drought stress reduced the yield of multiple plants at all sites, while increasing the proline content in the Chinese genotype. Foliar spray treatments, especially the combined application of Se, CPPU, and SLs, improved relative water content and mitigated drought-induced declines in chlorophyll content. The combined application of Se + SLs + CPPU under drought stress conditions enhanced Stevia leaf yield in the Indian genotype significantly. In addition, such treatments positively impacted steviol glycosides (SvGls) content and yield, especially under drought stress conditions. Comparing Stevia genotypes indicated the superior performance of the Indian genotype in terms of relative water content, photosynthetic pigments, as well as SvGls content and yield. However, the Chinese genotype exhibited superior enzyme activity levels. Based on the results, Se application under drought stress conditions enhances the activity of catalase and peroxidase, resulting in improving plant yield while mitigating the adverse effects of drought stress.