A novel series of metal(II) complexes (1–5) MII(L)2{Where M = Cu (1), Co (2), Mn (3), Ni (4) and Zn (5)} constructed from 2-(4-morpholinobenzylideneamino)phenol Schiff base ligand (HL) in a 1:2 M ratio and the spectral and analytical results put forward square planar geometry. Spectro-electrochemical, hydrodynamic, gel electrophoresis, and DNA binding/cleavage results for all the compounds demonstrate that complex (1) had excellent DNA binding/cleavage properties compared to other compounds. The observation also suggests that test compounds could intercalate with DNA, and the biothermodynamic property more strongly supports the stabilizing of the double helix DNA with the complexes. BSA binding constant results show that complex (1) exposes the best binding property via a static mode, which is further confirmed by FRET calculations. The DFT calculations and docking results for all compounds towards DNA, BSA and SARS-CoV-19 main protease (3CLPro), reveal the binding energies were in the range of −7.8 to −9.4, −6.6 to −10.2 and − 6.1 – −8.2 kcal/mol for all test compounds respectively. In this case, complexes showed favorable binding energies compared to free ligand, which stimulates further studies aimed at validating the predicted activity as well as contributing to tackling the current and future viral pandemics. The in-vitro antioxidant, antimicrobial, and anticancer results for all compounds revealed that copper complex (1) has better activity compared to others. This might result in an effective anticancer drug for future research, which is especially promising since the observed experimental results for all cases were in close agreement with the theoretical calculations. Among the synergistic experimental and computational investigations of the biomolecular interaction of morpholine scaffold transition metal(II) complexes towards DNA/BSA & SARS-CoV-19, the copper complex revealed excellent biological efficacy via intercalation, which may contribute to a novel class of anticancer agents in the future. Display omitted •Transition metal(II) complexes were constructed from morpholine scaffold ligand.•Spectroscopic & analytical results proposed that the complexes have a square planar geometry.•The metal complexes exhibit more potent antimicrobial, antioxidant, and anticancer activity than that of the free ligand. The copper complex acted as a good DNA intercalator.•The DFT & molecular docking results agreed well with the experimental results.•The copper complex has exposed the best anticancer efficacy compared to others, which may lead to promising anticancer agents.