c. 1300, splen, "non-glandular organ of the abdomen of a human or animal," also as the seat of melancholy, from Old French esplen, from Latin splen, from Greek σπλήν "the milt, spleen," from PIE *spelghn- "spleen, milt" (source also of Sanskrit plihan-, Avestan sperezan, Armenian p'aicaln, Latin lien, Old Church Slavonic slezena, Czech slezna, Lithuanian blužnis, Old Prussian blusne, Old Irish selg "spleen"). But the exact reconstruction is unclear.

The organ was regarded in old medicine as the seat of morose feelings and bad temper. Hence figurative sense of "violent ill-temper" (1580s, implied in spleenful); and thence Chapman's spleenless "mild, gentle; free from anger, ill-humor, malice, or spite" (1610s, in the literal sense from late 14c.), for which compare Greek eusplanchnos "having healthy intestines," also "compassionate."

A burst of adjectival forms in late 16c.-early 17c. for the figurative meaning yielded spleenative (1592), spleenatic (1621), spleenish (1610s), spleenful (1588), spleeny (1604), and later Keats uses spleenical.