In this article, the effect of the preparation methods of titanium pyrophosphate (TiPO) catalysts on their catalytic performances via the oxydehydrogenation (ODH) of n-butane has been investigated. The TiPO-A, TiPO-B, and TiPO-S catalysts have been prepared, respectively, by three synthesis methods: (1) liquid–solid, (2) coprecipitation, and (3) solid-state methods. The samples have been characterized by N₂-sorption, X-ray diffraction, inductively coupled plasma through the atomic emission spectroscopy, Fourier transform infrared, thermogravimetric analysis, differential scanning calorimetry, field emission scanning electron microscopy, and temperature-programmed desorption (NH₃ or CO₂). Fourier transform infrared and X-ray diffraction data indicate the presence of a pure TiP₂O₇ phase in TiPO-A and TiPO-S samples, whereas TiPO-B revealed the presence of an amorphous TiP₂O₇ and rutile TiO₂ phase. The coupled TGA/DSC curves showed that all catalysts are stable up to 600 °C. The catalytic testing, performed at 500 °C in ODH of n-butane, shows that the best yield (11.6%) is obtained over the TiPO-A catalyst, with 22.7% of butane conversion and 51.2% of total butene selectivity (whose 94.6% is the trans-2-butene), and seems to be an important result in this work. Only the TiPO-B1 catalyst produced butadiene with 1.7% (14.2% of ODH product) selectivity; this result is no less crucial.