Although Instagram is widely used among young people, it has only recently caught researchers’ attention. Following the perspective of the I-PACE model, the present study examined the relationship between neuroticism and problematic Instagram use (PIU) in Italian university students who had an Instagram account. We assumed that the relationship between neuroticism and PIU could be explained by direct and indirect paths, passing through Fear of Missing Out (FoMO) and motives for Instagram use. 362 Instagram users (72.1% female; Mage = 25.35, SD = 4.25) filled out a questionnaire assessing demographics, Instagram use features, Neuroticism, Problematic Instagram use, FoMO, and Motivations for Using Instagram. Results showed that neuroticism affected PIU only indirectly through FoMO, escapism and self-expression motives. Additionally, FoMO promoted higher levels of escapism and self-expression motives, increasing participants’ risk of PIU. This is the first study testing the mediating role of motives for using Instagram between personality predisposing factors and PIU. The findings provide new insights into the relationship between the factors that may promote PIU and have important clinical implications. These include the possibility for practitioners to prevent PIU more easily by acting on users’ motivations and cognitions, such as escapism, self-expession and FoMO, rather than working on predisposing personality factors, that are usually more stable over time.