Objective: The bacterial phylum Deinococcus-Thermus includes two groups of bacterial genomes i.e., radiation-resistant mesophilic Deinococcales and radiation-sensitive hyperthermophilic Thermales. Our endeavor is to address the factors influencing the niche-specific molecular evolution of this immensely interesting bacterial phylum. Methods: An extensive comparative analysis of codon and amino acid usage patterns, aided by multivariate statistical techniques, was carried out in our chore. Evolutionary analysis was also executed to investigate the riddles of adaptive strategy opted by this fascinating pool of microbes. Results: Significant differences in synonymous codon usage bias and amino acid usage patterns have been reported between the hyperthermophilic, radiation-sensitive Thermales genomes and mesophilic, radiation-resistant Deinococcales genomes. The amino acid usage patterns of radiation-resistant, mesophilic organisms under study are primarily influenced by their mode of adaptation to radiation. Core proteins from the group show signatures of both purifying as well as positive selection. Housekeeping genes tend to be under the influence of strong purifying selection, whereas, proteins mainly associated with defense mechanisms and secretion are inferred to be under the force of positive adaptation. Conclusion: G+C compositional bias has been revealed to be a crucial determinant in shaping the codon usage signature. Investigation at proteomic level reflects the fact that genomes of the phylum Deinococcus-Thermus have distinct amino-acid compositional feature, physicochemical and structural trait and varying degrees of stability of their core proteome, according to their adaptation towards radiation and variable temperature stresses. The evolutionary analysis hints to the adaptive strategy that may be employed by these groups of microbes to survive against extremities of temperature and radiation.