In the piercing process of large-diameter seamless steel pipe blanks after heating, severe lateral cracks easily occur on the surface of pierced pipe blanks owing to the effects of the large temperature difference and thermal stress during the heating phase, influencing the finished product ratio and the safety and stability of use. Therefore, obtaining pipe blanks with uniform temperature distributions and low thermal stress peaks is the basis for the quality assurance of seamless pipes. In this paper, a study was conducted with large-diameter TP321 seamless pipe blanks with an example. The heating process of the pipe blank was investigated from two perspectives, temperature fields and thermal stress fields. Moreover, the effects of heating rate, initial furnace temperature, and hot-charging temperature were quantitatively analyzed. It was found that the peaks of the temperature difference and thermal stress both occurred at the early stage of heating. The temperature field and thermal stress distribution of the pipe blank gradually changed during heating. At the initial stage of heating, the temperature at the outer diameter edge was the highest, and the maximum thermal stress zones were concentrated on the inner hole edge and external surface. At the late stage of heating, the highest temperature zone and the maximum thermal stress zone were both focused on the inner hole surface. Lower initial furnace temperature and higher hot-charging temperature were more conducive to decreasing the maximum temperature difference and peak thermal stress, while the changes in heating rate had insignificant effects.