The effect of isotropic strain on the band structures and thermoelectric properties of 2,7-dioctylbenzothieno[3,2-b]benzothiophene (C8-BTBT) modified with hydroxyl (–OH), amino (–NH2), and methyl (–CH3) groups at room temperature have been investigated by first-principles calculations. We found that isotropic strain modified the Fermi levels and bandgaps of the C8-BTBT-based organic semiconductors. The variations of the dimensionless figure of merit (zT) values of the N-type semiconductors are greater than those of the P-type semiconductors. The thermoelectric properties were calculated using the BoltzTraP code. The results show that there is an optimal carrier concentration (N) to give the maximum zT value of the C8-BTBT-based organic semiconductor. The maximum zT value of the N-type semiconductor is 0.41 for OH-modified C8-BTBT. For the P-type semiconductor, the maximum zT value is 0.36 for CH3-modified C8-BTBT. We also found that NH2-modified C8- BTBT has poor thermoelectric properties, which means that the –NH2 group may not be the optimal choice for C8-BTBT in thermoelectric applications.