Alcohol, nicotine, and cannabis are among the most commonly used drugs. A prolonged and combined use of these substances can alter normal brain wiring in different ways depending on the consumed cocktail mixture. Brain connectivity alterations and their change with time can be assessed using functional magnetic resonance imaging (fMRI) because of its spatial and temporal content. Here, we estimated dynamic functional network connectivity (dFNC) as derived from fMRI data to investigate the effects of single or combined use of alcohol, nicotine, and cannabis. Data from 534 samples were grouped according to their substance use combination as controls (CTR), smokers (SMK), drinkers (DRN), smoking-and-drinking subjects (SAD), marijuana users (MAR), smoking-and-marijuana users (SAM), marijuana-and-drinking users (MAD), and users of all three substances (ALL). The DRN group tends to exhibit decreased connectivity mainly in areas of sensorial and motor control, a result supported by the dFNC outcome and the alcohol use disorder identification test. This trend dominated the SAD group and in a weaker manner MAD and ALL. Nicotine consumers were characterized by an increment of connectivity between dorsal striatum and sensorimotor areas. Where possible, common and separate effects were identified and characterized by the analysis of dFNC data. Results also suggest that a combination of cannabis and nicotine have more contrasting effects on the brain than a single use of any of these substances. On the other hand, marijuana and alcohol might follow an additive effect trend. We concluded that all of the substances have an impact on brain connectivity, but the effect differs depending on the dFNC state analyzed.