Endophytic fungi are important sources of structurally and biologically diverse secondary metabolites. Recent studies demonstrated that some endophytic fungi can produce bioactive compounds that are identical or similar to compounds derived from the host plants. Examples of such compounds include paclitaxel (Taxus brevifolia), podophyllotoxin (Podophyllum peltatum), camptothecin (Camptotheca acuminata), hypericin and emodin (Hypericum perforatum), ginkolide B (Ginkgo biloba), and piperin (Piper longum L.). In our search for novel natural products of endophytic fungi associated with medicinal plants, we isolated an α-pyrone polyketide with the uncommon bicyclo[4.2.0]octadiene structure from a Penicillium fungus separated from the surface-sterilized healthy leaves of Catharanthus roseus. Continuing our search, we found an endophytic Mycosphaerella fungus isolated from the surface-sterilized healthy leaves of Aloe arborescens, a traditionally used medicinal plant. Recently, we have applied epigenetic modifiers, such as histone deacetylase (HDAC) and DNA methyl transferase inhibitors, to fungal cultivations, and succeeded to isolate a variety of new secondary metabolites. Consequently, Mycosphaerella fungus was cultivated in the presence of nicotinamide (an NAD+ -dependent HDAC inhibitor), leading to the isolation of three new short-branched fatty acid dimers, named as mycosphines A–C (1–3), along with a known 3-(2-butyl)-6-ethyl-5-hydroxy-2-methoxy-6-methyl-cyclohex-2-enone (mycosphine D, 4). Herein, we describe the structures of 1–4, elucidated by spectroscopic analysis, single crystal X-ray diffraction, and vibrational circular dichroism (VCD) analysis.