We aimed to explore the morphological evolution of recent small subcortical infarcts (RSSIs) over 15 months. Moreover, we hypothesized that quantitative lesion apparent diffusion coefficient (ADC) values and serum neurofilament light (NfL) levels predict subsequent lacunar cavitation. We prospectively studied 78 RSSI patients, who underwent pre-defined follow-up investigations three and 15 months poststroke using 3 T MRI including high-resolution T1 sequences. To identify potential predictors of cavitation, we determined RSSI size and quantitative ADC values, and serum NfL using the SIMOA technique. The majority of RSSIs showed cavitation at three months ( n = 61, 78%) with only minimal changes regarding cavitation status thereafter. The maximum axial lacunar diameter decreased from 8 mm at three to 7 mm at 15 months ( p < 0.05). RSSIs which cavitated had lower lesional ADC values and were associated with higher baseline NfL levels compared to those without cavitation, but did not differ regarding lesion size. In logistic regression analysis, only baseline NfL levels predicted cavitation ( p = 0.017). In this prospective study using predefined high-resolution MRI protocols, the majority of RSSIs evolved into lacunes during the first three months poststroke with not much change thereafter. Serum NfL seems to be a promising biomarker for more advanced subsequent tissue destruction in RSSIs.