Understanding the vertical penetration process of submarine pipelines is of fundamental significance for the reasonable assessment of the initial pipeline embedment during installation and safety and stability during service. Geotechnical centrifuge model tests, combined with discrete element method modelling were conducted to investigate penetration resistance evolution characteristics and mesoscopic mechanism of submarine pipeline in sand with different densities under the real stress level. The test results show that for the medium-dense sand, the pipe penetration resistance−embedment curve shows a hardening trend. On the other hand, for the dense sand, the pipe penetration resistance−embedment curve exhibits a periodic softening trend; moreover, the deeper the embedment is, the greater the degree of softening becomes. Discrete element modelling results demonstrate that the difference in pipe penetration resistance−embedment curves is induced by different soil movement and failure modes when pipe penetrates in sands with different densities. The pipe penetration resistance evolution characteristics are closely related to the formation and development of shear band in sand. The evolution characteristics of penetration resistance with embedment should be fully considered when evaluating pipe embedment in dense sands using the current design specification for submarine pipelines. More specifically, the pipe embedment should be reasonably estimated based on the upper and lower limits of calculation results, when the preliminarily estimated pipe embedment is larger than one tenth of the pipe diameter.