Lasiodiplodiapyrones A and B (<b>1</b> and <b>2</b>), two new preussomerin derivatives, possessing an unexpected 6-methyl-4<i>H</i>-furo[3,2-<i>c</i>]pyran-4-one moiety and a highly functionalized conjoint and complicated polycyclic ring system, along with two known congeners (<b>3</b> and <b>4</b>), were isolated from the fungus <i>Lasiodiplodia pseudotheobromae</i>. Their structures including absolute configurations were determined by spectroscopic analyses, Mosher's method, and ECD calculations. A biosynthetic pathway was proposed to explain the origin of lasiodiplodiapyrones A and B as well as their relationship with preussomerins. Compounds <b>1</b>-<b>4</b> showed suppressive effects on the production of NO with IC<sub>50</sub> values of 4.8 ± 0.3, 8.5 ± 1.1, 5.9 ± 0.8, and 12.8 ± 1.3 μM, respectively.