This study investigates the role of *StMAPKK5* in drought and salt stress response in potato. *StMAPKK5* was found to be highly expressed in leaves under both drought and salt stress conditions. Overexpression of *StMAPKK5* in potato plants enhanced their drought and salt tolerance, as evidenced by increased relative water content, antioxidant enzyme activities (SOD, CAT, POD), and proline content, while reducing malondialdehyde (MDA) content. Subcellular localization revealed that *StMAPKK5* is localized in the nucleus, cytoplasm, and cell membrane. Yeast two-hybrid and bimolecular fluorescence complementation (BiFC) assays identified four interacting proteins: StMYB19, StZFP8, StPUB-like, and StSKIP19. These proteins were found to play significant roles in drought and salt tolerance, with StMYB19 showing synergistic effects with *StMAPKK5*. The study provides insights into the regulatory mechanisms of *StMAPKK5* in potato stress response and suggests its potential as a target for improving potato stress tolerance.This study investigates the role of *StMAPKK5* in drought and salt stress response in potato. *StMAPKK5* was found to be highly expressed in leaves under both drought and salt stress conditions. Overexpression of *StMAPKK5* in potato plants enhanced their drought and salt tolerance, as evidenced by increased relative water content, antioxidant enzyme activities (SOD, CAT, POD), and proline content, while reducing malondialdehyde (MDA) content. Subcellular localization revealed that *StMAPKK5* is localized in the nucleus, cytoplasm, and cell membrane. Yeast two-hybrid and bimolecular fluorescence complementation (BiFC) assays identified four interacting proteins: StMYB19, StZFP8, StPUB-like, and StSKIP19. These proteins were found to play significant roles in drought and salt tolerance, with StMYB19 showing synergistic effects with *StMAPKK5*. The study provides insights into the regulatory mechanisms of *StMAPKK5* in potato stress response and suggests its potential as a target for improving potato stress tolerance.