We studied the effects of different preparation method and In-substitution on its crystal structure and thermoelectric (TE) properties of polycrystalline GeSb<sub>6</sub>Te<sub>10</sub>. Firstly, the effects of spark plasma sintering (SPS) on the crystal structure and elemental distribution of GeSb<sub>6</sub>Te<sub>10</sub> were discussed. GeSb<sub>6</sub>Te<sub>10</sub> consolidated using SPS consisted of a mixture of GeSb<sub>6</sub>Te<sub>10</sub>-type homologous and Sb<sub>2</sub>Te<sub>3</sub>-type tetradymite structures, whereas the sample prepared by melting had a single homologous structure. The elemental compositional deviation from the nominal composition of the sample prepared by SPS was wider than that prepared by melting. This implies that SPS promoted atomic diffusion and rearrangement of elements, leading to a substantial change in the crystal structure and elemental distribution of GeSb<sub>6</sub>Te<sub>10</sub>. Secondly, the effects of In-substitution on the crystal structure and TE properties of GeIn<sub><i>x</i></sub>Sb<sub>6−<i>x</i></sub>Te<sub>10</sub> (<i>x</i>=0, 0.18, 0.3, and 0.6) prepared by melting were discussed. Rietveld and Le Bail analyses showed that all compositions crystallized in trigonal structures with a 51-layer period. Substituting In decreased both the lattice and electronic thermal conductivity, as well as markedly increased the Seebeck coefficient. We ascribed this increase to increases in the effective mass of the carriers, likely caused by the formation of additional energy states near the Fermi level. In GeIn<sub>0.6</sub>Sb<sub>5.4</sub>Te<sub>10</sub>, we found a maximum dimensionless figure of merit: <i>ZT</i><sub>max</sub> of 0.75 at 710 K, 1.9 times higher than that of GeSb<sub>6</sub>Te<sub>10</sub>.<br>