Plants require different inorganic minerals in an appropriate amount for growth; however, imbalance can limit growth and productivity. Heavy metal accumulation causes toxicity and generates signalling crosstalk with reactive oxygen species (ROS), phytohormones, genes and transcription factors (TFs). The MYB (myeloblastoma) TFs participate in plant processes such as metabolism, development, cell fate, hormone pathways and responses to stresses. This is the first report towards characterisation of R2R3-type MYB TF, SbMYB15, from succulent halophyte Salicornia brachiata Roxb. for heavy metal tolerance. The SbMYB15 showed >5-fold increased transcript expression in the presence of CdCl2 and NiCl2•6H2O. The constitutive overexpression of SbMYB15 conferred cadmium and nickel tolerance in transgenic tobacco, with improved growth and chlorophyll content. Further, the transgenics showed reduced generation of reactive oxygen species (H2O2 and O2•-) as compared with the wild-type (WT) with both Cd2+ and Ni2+ stress. Transgenics also showed low uptake of heavy metal ions, increased scavenging activity of the antioxidative enzymes (CAT and SOD) and higher transcript expression of antioxidative genes (CAT1 and MnSOD). Thus, the present study signifies that SbMYB15 can be deployed for developing heavy metal tolerance in crop plants via genetic engineering.