Quinolones are a widely used class of antibacterial agents characterized by overall favourable pharmacokinetic and pharmacodynamic characteristics. Unfortunately, both nosocomial and community acquired resistances to these agents are increasing. Thorough structure–activity relationship (SAR) studies have demonstrated that even drastic manipulation of the quinolone scaffold may lead to compounds maintaining antibacterial activity and avoiding mechanisms of resistance. We herein report the design and synthesis of a series of substituted 2,1-benzothiazine 2,2-dioxide derivatives designed as quinolone-like analogues, with the aim to further expand the SAR for this antibacterial class as well as to assay their capability of inhibiting the S. aureus NorA efflux pump. Although none of the new compounds evaluated showed any appreciable intrinsic antibacterial activity, the 2,1-benzothiazin-4-one 2,2-dioxide derivatives 17 and 18 were able to restore, in a concentration-dependent manner, the antibacterial activity of ciprofloxacin (CPX) against the norA-overexpressing S. aureus strain SA-K2378. Thus, these compounds have emerged as new hits in the search for novel efflux pump inhibitors useful for limiting the clinical impact of efflux-related quinolone resistance.