Euphorbia peplus has been used in traditional medicine to treat asthma and psoriasis. Three highly modified diterpenoids, namely, pepluacetal (1) and pepluanol A-B (2-3), have been isolated and identified from this plant. Compounds 1-3 exhibit unprecedented 5/4/7/3, 5/6/7/3, and 5/5/8/3 ring systems, respectively. Their structures with absolute configurations were determined by spectroscopic analyses, X-ray crystallography, and electronic circular dichroism calculations. Since Kv1.3 is a validated target for the treatment of autoimmune diseases, such as multiple sclerosis, type-1 diabetes, asthma, and psoriasis, Kv1.3 was studied in terms of its response to the new compounds. All three compounds inhibit Kv1.3, with compound 3 being the most effective with an IC50 value of 9.50 μM.