The domain of unknown function (DUF221 domain-containing) proteins regulates various aspects of plant growth, development, responses to abiotic stresses, and hormone transduction pathways. To understand the role of DDP proteins in tomato, a comprehensive genome-wide analysis was performed in the tomato genome. A total of 12 DDP genes were identified and distributed in 8 chromosomes in the tomato genome. Phylogenetically all SlDDPs were clustered into four clades, subsequently supported by their gene structure and conserved motifs distribution. The SlDDPs contained various cis-acting elements involved in plant responses to abiotic and various phytohormones stresses. The tissue-specific expression profile analysis revealed the constitutive expression of SlDDPs in roots, leaves, and developmental phases of fruit. It was found that SlDDP1, SlDDP3, SlDDP4, SlDDP9, SlDDP10, and SlDDP12 exhibited high expression levels in fruits at different development stages. Of these genes, SlDDP12 contained ethylene (ERE) responsive elements in their promoter regions, suggesting its role in ethylene-dependent fruit ripening. It was found that a single SlDDP induced by two or more abiotic and phytohormone stresses. These include, SlDDP1, SlDDP2, SlDDP3, SlDDP4, SlDDP7, SlDDP8, and SlDDP10 was induced under salt, drought, ABA, and IAA stresses. Moreover, tomato SlDDPs were targeted by multiple miRNA gene families as well. In conclusion, this study predicted that the putative DDP genes might help improve abiotic and phytohormone tolerance in plants, particularly tomato, rice, and other economically important crop plant species.