When cold atmospheric plasma comes into contact with water and biological media, antimicrobial or antitumor effects are induced, representing great potential for applications in biomedicine and agriculture. The need to control and tune the chemical composition and biomedical effects of plasma activated water/media (PAW/PAM) is emerging. By comparing two nonthermal air plasma sources, streamer corona and transient spark, interacting with water in open and closed reactors, and by enhancing the plasma–liquid interaction by water electrospray through these discharges, we demonstrate that the plasma gaseous products strongly depend on the discharge regime, its deposited power and gas flow conditions. The streamer corona strongly leads to the formation of ozone and hydrogen peroxide, while the more energetic transient spark leads to nitrogen oxides and hydrogen peroxide. The gaseous products then determine the chemical properties of the PAW and the dominant aqueous reactive oxygen and nitrogen species (RONS). The production of hydrogen peroxide depends on water evaporation and hydroxyl radical formation, which is determined by the discharge power. A transient spark produces higher concentrations of gaseous and aqueous RONS and induces stronger antibacterial effects than a streamer corona; however, the RONS production rates per joule of deposited energy are comparable for both studied discharge regimes. The net production rate per joule of gaseous nitrogen oxides strongly correlates with that of aqueous nitrites and nitrates. The antibacterial effects of the PAW tested on Escherichia coli bacteria are determined by the aqueous RONS: in the lower power streamer corona, this is ascertained mainly by the dissolved ozone and hydrogen peroxide, and in the higher power transient spark, by the combination of hydrogen peroxide, nitrite and acidic pH, while in the transient spark in the closed reactor it is determined by the acidified nitrites present.