Fast real-time processing of external information by the brain is vital to survival in a highly dynamic environment. A ubiquitous information medium used by humans is spoken language, but the neural dynamics of its comprehension is still poorly understood. Here, we scrutinized the earliest electrophysiological activity elicited in the human brain by spoken words and matched meaningless word-like stimuli using a lexical auditory oddball paradigm, an established technique for investigating cortical activation patterns underlying early automatic stages of language processing. We show that the earliest cortical reflection of word comprehension takes place during the electrophysiological P1 evoked response, at about 30 ms following the word disambiguation point, and takes the form of an enhanced brain activation for familiar meaningful words, even when they are presented outside the focus of attention. This previously unknown ultra-early lexicality effect is underpinned by left temporo-frontal cortical circuits and likely reflects a first-pass automatic lexical access that precedes later stages of lexical and semantic processing described in previous literature. The results suggest that the brain operates with maximum speed and efficiency to extract meaningful (including linguistic) information from the sensory input, which is a neurobiological capacity essential for timely and appropriate reactions to external events.