The present study aimed to investigate the neural changes related to the early stages of sign language vocabulary learning. Hearing non-signers were exposed to Catalan Sign Language (LSC) signs in three laboratory learning sessions over the course of a week. Participants completed two priming tasks designed to examine learning-related neural changes by means of N400 responses. In a semantic decision task, participants evaluated whether written Catalan word pairs were semantically related or not. The experimental manipulation included prime-target phonological overlap (or not) of the corresponding LSC sign translations. In a LSC primed lexical decision task, participants saw pairs of signs and had to determine if the targets were real LSC signs or not. The experimental design included pairs of signs that were semantically related or unrelated. The results of the LSC lexical decision task showed N400 lexicality and semantic priming effects in the third session. Also in the third session, N400 effects related to the activation of LSC phonology were observed during word processing in the semantic decision task. Overall, our findings suggest rapid neural changes occurring during the initial stages of intensive sign language vocabulary training. The results are discussed in relation to the temporality of lexicality and semantic effects, as well as their potential relation to linguistic features of sign languages.