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 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.