The phosphatidylinositol 3-kinase (PI3K)/Akt intracellular signaling pathway plays important roles in both normal physiological and pathogenic processes by regulating the expression of genes involved in cell survival, differentiation, growth, movement, and apoptosis. In particular, the PI3K/Akt signaling pathway has been implicated in the development and progression of haptic fibrosis. In this review, we summarize the current knowledge of the mechanisms by which PI3K/Akt signal transduction regulates extracellular matrix degradation, hepatic stellate cell activation, and sinusoidal capillarization, all of which play important roles in the formation of hepatic fibrosis. This information not only reveals the complex interplay of mulitple cellular processes and signaling factors underlying the disease condition, but also highlights the potential therapeutic benefit of inhibiting the PI3K/AKT pathway to prevent and treat liver fibrosis.