Reusing reclaimed water is of paramount importance to achieve the 2030 Agenda for Sustainable Development Goals 6 and 13. In Europe, a recent Regulation set minimum requirements for water reuse in agriculture. However, some challenges remain considering microbial risks and their prevention. In this study, two urban wastewater treatment plants (WWTPs) were investigated from the perspective of reuse. A five-year investigation was performed on routine monitoring parameters collected under different weather conditions (wet/dry) and treatments (chlorination/non-chlorination) in inlet and outlet samples. Moreover, a three-month investigation focused on microbial parameters, including indicators, index pathogens (Human Adenovirus—HAdV, Salmonella spp.), and other viral pathogens (norovirus, enterovirus, and SARS-CoV-2). The long-term study revealed the compliance of both WWTPs for chemical parameters (organic substances and solids) in more than 90% of samples, whereas for Escherichia coli, the compliance ranged from 96.1% with chlorination under dry weather to 16.7% without chlorination in wet days. E. coli was positively associated with chemical oxygen demand (COD), which could be a promising and online measurable proxy of E. coli. The study on microbial performance demonstrated sound reliability in detecting E. coli as a suitable surrogate for Salmonella in chlorinated effluents, but neither bacterial nor viral indicators are able to represent HAdV. Although chlorination was able to remove most of the pathogens considered, the compliance with microbial indicators seems insufficient to represent viral water safety.