Novel Schiff bases of metformin hydrochloride and ()-nitrobenzaldehyde were synthesized by employing two efficient environmentally friendly methods, namely, stirring and microwave-assisted methods using water as the solvent. The advantage of microwave irradiation over the other methods was represented in the reduction of reaction time and wastes, and good yields; however, water in both methods plays the role of eco-friendly solvent. The structural properties of the ()-isomer products were analyzed by elemental analysis, Fourier transform infrared (FTIR) spectroscopy, UV-Visible (UV-Vis) spectroscopy, H nuclear magnetic resonance (NMR) spectroscopy, C NMR spectroscopy, mass spectroscopy, and differential scanning calorimetry (DSC). The newly synthesized compounds were screened for their antibacterial activity against selected Gram-positive (ATCC 25923, ATCC 43300, and ATCC 29212) and Gram-negative (ATCC 25922, ATCC 27853, and ATCC 700603) bacteria using the agar well diffusion method. Compared with the standard drug streptomycin, both Schiff bases exhibited moderate bactericidal activity against the tested bacteria with higher values of -nitro compared with the -nitro isomer; however, no effect on ATCC 43300 and ATCC 27853 was observed under the experimental conditions employed.