Systemic sclerosis (SSc) or scleroderma is a chronic multi-organ autoimmune disease characterized by vascular, immunological, and fibrotic abnormalities. The etiology of SSc is unknown, but there is growing evidence that dysfunction of the endocannabinoid system (ECS) plays a critical role in its development. Since the semi-synthetic cannabinoquinoid VCE-004.8 could alleviate bleomycin (BLM)-induced skin fibrosis, we have investigated an oral lipid formulation (EHP-101) of this dual PPARγ/CB2 receptors activator for the prevention of skin- and lung fibrosis and of collagen accumulation in BLM challenged mice. Immunohistochemistry analysis of the skin showed that EHP-101 could prevent macrophage infiltration as well as the expression of Tenascin C (TNC), vascular cell adhesion molecule 1 (VCAM1), and the α-smooth muscle actin (SMA). EHP-101 could also prevent the reduced expression of vascular CD31 typical of skin fibrosis. RNAseq analysis of skin biopsies showed a clear effect of EHP-101 in the inflammatory and epithelial-mesenchymal transition transcriptomic signatures. TGF-β-regulated genes [matrix metalloproteinase-3 (Mmp3), cytochrome b-245 heavy chain (Cybb), lymphocyte antigen 6E (Ly6e), vascular cell adhesion molecule-1 (Vcam1) and Integrin alpha-5 (Itga5)] were induced in BLM mice and repressed by EHP-101 treatment. By intersecting differentially expressed genes in EHP-101-treated mice with a dataset of human scleroderma intrinsic genes, 53 overlapped genes were discovered, including biomarkers of SSc like the C-C motif chemokine 2 (Ccl2) and the interleukin 13 receptor subunit alpha 1 (IL-13Ra1) genes. Taken together, these data provide a rationale for further developing VCE-004.8 as an orally active agent to alleviate scleroderma and, possibly, other fibrotic diseases as well.