Adipogenesis involves preadipocyte proliferation and differentiation into mature adipocytes, with dysregulation of this process being associated with changes in metabolic health. Here, we aimed to evaluate the effect of IGFBP4 knockdown (KD) on human preadipocytes and define if this altered IGF1 signaling. We assessed proliferation, adipogenic differentiation, gene expression, and the activation of the IGF1 receptor (IGF1R)/AKT pathway across different human adipocyte models. Our findings show IGFBP4 KD impaired proliferation and caused a reduction in IGF1R and phosphorylated AKT (Ser473) proteins, although no difference in adipogenic differentiation was observed. Furthermore, while adding recombinant human IGFBP4 did not reverse this effect, protein synthesis inhibition abolished IGFBP4 KD-mediated IGF1R downregulation when cotreated with a proteasomal inhibitor but not with a lysosomal inhibitor. We conclude that IGFBP4 knockdown is associated with IGF1R downregulation, impaired AKT phosphorylation, and suppressed proliferation, suggesting IGFBP4 is a critical regulator of IGF1R homeostasis in human preadipocytes.