The effects of tetrakis(1-methylpyridinium-4-yl)porphyrinatomercury(II) [ Hg ( TMPyP )]^4+^(6) along with [ Pb ( TMPyP )]^4+^(7), [ Cd ( TMPyP )]^4+^(8), and [ H~2~( TMPyP )]^4+^(1) (free base porphyrin) on DNA cleavage by Haemophilus aegyptius (HaeIII) have been studied using gel electrophoresis, UV-vis absorption spectroscopy, and circular dichroism (CD) spectroscopy. The gel electrophoresis results indicate that in the absence of 6, HaeIII restriction enzyme could not cleave plasmid DNA at a low concentration of 0.2 units ΞΌl^-1^after 1 h incubation at 37 Β°C. However, DNA cleavage occurred in the presence of 6 at the concentrations of 1.0 Γ 10^-6^and 1.0 Γ 10^-7^M and 0.2 units ΞΌl^-1^of HaeIII under the same conditions. In addition, acceleration of DNA cleavage occurred at a higher concentration of HaeIII (0.4 units ΞΌl^-1^) in the presence of a wider concentration range of 6 from 1.0 Γ 10^-5^to 1.0 Γ 10^-7^M . 8, 7, and 1 could not enhance DNA cleavage in the presence of HaeIII (0.2 units ΞΌl^-1^). However, when the concentration of HaeIII was increased to 0.4 units ΞΌl^-1^, only 8 inhibited DNA cleavage by HaeIII at higher concentrations (1.0 Γ 10^-5^-10^-6^M ) whereas 6, 7, and 1 did not. The UV-vis and CD spectroscopic results indicate that these porphyrins interact differently with DNA based on their binding modes. 6 enhanced DNA cleavage due to the synergistic effect of the Hg^2+^ions and the free base porphyrin 1 that dissociated from the mercury(II) porphyrin complex upon binding to DNA which resulted in the enhanced transformation of the DNA conformation from the original B-form to a Z-like conformation, while 8 inhibited HaeIII activity at higher concentrations and 7 and 1 neither enhanced nor inhibited DNA cleavage. A mechanism for this phenomenon is suggested.