The interaction between domoic acid(DA) and 18-mer double-stranded DNA(dsDNA) was investigated by using microchip-based non-gel sieving electrophoresis. For the 18-mer dsDNA with a sequence of 3′-GCATTGGTTGACGTTGCA-5′, the amount of free dsDNA decreases with the increase of the added DA and also with the increase of reactive time. Meanwhile, the newly-produced two peaks were observed. The experimental results show that there is a strong interaction between DA and the 18-mer dsDNA. DA makes the degradation of the 18-mer dsDNA. The non-gel sieving electrophoresis on microchip is a rapid, convenient, highly sensitive method for studying the interaction between DNA and small molecules.