With the increasing depth of marine oil and gas exploitation, more requirements have been proposed on the structure of deep-sea oil pipelines. The influencing factors of lateral buckling of a pipe-in-pipe (PIP) structure containing initial imperfections and its critical force were investigated in this study by conducting an experiment, a finite element analysis, and a theoretical derivation. The change laws on the influence of initial imperfections of the PIP structure during thermal loading were revealed through an experimental study by using imperfection amplitude and wavelength as parameters. Appropriate finite element models were established, and the influences of initial imperfections, pipe-soil interaction, and the height and the number of centralizers on the global buckling critical force of the PIP structure were analyzed. The formulas of global buckling critical force of inner and outer pipes and that under pipe-soil interaction was obtained by using a theoretical derivation method. A comparative verification with experimental and finite element (FE) models result was conducted, which provided a corresponding basis for steel pipeline design.