With the ever-growing problem of antibiotic resistance, developing antimicrobial strategies is urgently needed. Herein, a hydrophobic drug delivery nanocarrier is developed for combating planktonic bacteria that enhances the efficiency of the hydrophobic antimicrobial agent, Triclosan, up to a 1000 times. The poly( N -isopropylacrylamide- co - N -[3-(dimethylamino)propyl]methacrylamide), p(NIPAM- co -DMAPMA), based nanogel is prepared via a one-pot precipitation polymerization, followed by quaternization with 1-bromododecane to form hydrophobic domains inside the nanogel network through intraparticle self-assembly of the aliphatic chains (C12). Triclosan, as the model hydrophobic antimicrobial drug, is loaded within the hydrophobic domains inside the nanogel. The nanogel can adhere to the bacterial cell wall via electrostatic interactions and induce membrane destruction via the insertion of the aliphatic chains into the cell membrane. The hydrophobic antimicrobial Triclosan can be actively injected into the cell through the destroyed membrane. This approach dramatically increases the effective concentration of Triclosan at the bacterial site. Both the minimal inhibitory concentration and minimal bactericidal concentration against the Gram-positive bacteria S. aureus and S. epidermidis decreased 3 orders of magnitude, compared to free Triclosan. The synergy of physical destruction and active nanoinjection significantly enhances the antimicrobial efficacy, and the designed nanoinjection delivery system holds great promise for combating antimicrobial resistance as well as the applications of hydrophobic drugs delivery for many other possible applications.