The goal of this study was to characterize changes in components and toxicological properties of PM2.5 during the nationwide 2019-Coronavirus (COVID-19) lockdown restrictions in Milan, Italy. Time-integrated PM2.5 filters were collected at a residential site in Milan metropolitan area from April 11th to June 3rd at 2020, encompassing full-lockdown (FL), the followed partial-lockdown (PL2), and full-relaxation (FR) periods of COVID-19 restrictions. The collected filters were analyzed for elemental and organic carbon (EC/OC), water-soluble organic carbon (WSOC), individual organic species (e.g., polycyclic aromatic hydrocarbons (PAHs), and levoglucosan), and metals. According to online data, nitrogen dioxide (NO2) and benzene (C6H6) levels significantly decreased during the entire COVID-19 period compared to the same time span in 2019, mainly due to the government-backed shutdowns and curtailed road traffic. Similarly, with a few exceptions, surrogates of tailpipe emissions (e.g., traffic-associated PAHs) as well as re-suspended road dust (e.g., Fe, Mn, Cu, Cr, and Ti) were relatively lower during FL and PL2 periods in comparison with year 2019, whereas an increasing trend in mass concentration of mentioned species was observed from FL to PL2 and FR phases due to the gradual lifting of lockdown restrictions. In contrast, comparable concentrations of ambient PM2.5 and black carbon (BC) between lockdown period and the same time span in 2019 were attributed to the interplay between decreased road traffic and elevated domestic biomass burning as a result of adopted stay-home strategies. Finally, the curtailed road traffic during FL and PL2 periods led to ~25% drop in the PM2.5 oxidative potential (measured via 2′,7′-dichlorodihydrofluorescein (DCFH) and dithiothreitol (DTT) assays) with respect to the FR period as well as the same time span in 2019. The results of this study provide insights into the changes in components and oxidative potential of PM2.5 in the absence of road traffic during COVID-19 restrictions.