The methods disclosed herein are directed towards improving ablation efficiency associated with applying nanosecond electric pulses (nsEP) to tissue. In particular, applying nsEP to tissue can open pores in the cellular membranes of the tissue. These pores can be kept open longer by cooling the tissue. The combined application of nsEP and the cooling of tissue may have synergistic effects on triggering apoptosis of cells in the tissue. This allows for numerous practical benefits associated with nsEP-based tissue ablation to be realized. For instance, nsEP of lower pulse strength or lower numbers of pulses to be used, which can be provided by smaller pulse generators operating on less power.