Liver fibrosis (LF) is a chronic disease, induced by various toxic stress factors associated with the regeneration processes and triggering scar tissue formation. Progression of LF usually results in chronic inflammation, fatal liver cirrhosis, and/or the development of hepatic cancer. Herein, we describe the evaluation of the anti-fibrotic effects of novel colchicine derivatives, namely, a water-soluble colchicinoid (4) and a retinoid acid-colchicine conjugate (5) in its liposomal formulation (L2) to target hepatic stellate cells (HSC). The model LF was induced in mice by i.p. injections of CCl. The treatment was initiated after CCl discontinuation, when LF progression was established by histology and liver enzyme levels. Both prodrugs stimulated liver regeneration as was evidenced by blood levels of matrix metalloproteases (MMP), chemokines, and cytokines as well as by fibrinogen gene expression. However, the effect of the preparation 4 was associated with the treatment-induced inflammation, elevated levels of MMPs, chemokines, and proinflammatory cytokine IL-2, IL-6, IL-22, IL-13. The effect of L2 was mild however more efficient possibly due to the targeting the HSCs. Both 4 and L2 are suitable for practical treatment of LF with appropriate doses. The liposomal formulation L2 demonstrated an improved safety profile.