Purpose: To explore the contribution of paired-related homeobox 1-positive (Prrx1+) cells to the implant-induced osseointegration process in adult alveolar bone and the potential underlying mechanisms. Materials and Methods: Crerecombinase-induced lineage tracing and cell ablation were conducted in a murine dental implant model. Scratch and transwell assays were used to assess MC3T3-E1 cell migration after paired-related homeobox 1 overexpression. Single-cell RNA sequencing was applied to identify potential genes involved in Prrx1+ cell–driven osteogenesis. Results: Prrx1+ cells were observed to accumulate in the peri-implant area in a time-dependent manner; the number of these cells was found to reach its maximum on day 14. Osseointegration in mice was noticeably impaired after ablation of Prrx1+ cells. Further, it was discovered that Prrx1 promotes MC3T3-E1 cell migration, a process which is indispensable for sound healing of peri-implant tissue. Finally, semaphorin 3C (Sema3C) was detected exclusively and abundantly expressed by Prrx1+ cells. Knockdown of Sema3C in Prrx1+ cells significantly weakened their osteogenic potential. Conclusions: Our data suggest that Prrx1+ cells contribute to the osseointegration process under stress stimulation and Sema3C may play a critical role in Prrx1+ cell–driven osteogenesis. Prrx1 could significantly promote MC3T3-E1 cell migration.