In situ electrochlorination can offer an efficient and feasible solution to enable decentralized water disinfection. Unfortunately, there has been only a limited number of studies exploring single-pass flow cell systems with representative flowrates used at household level, particularly under varying chloride concentrations. This work aims to assess anode materials in a single pass and examine the impact of cross velocity, current density, and chloride concentration on various responses such as chlorine production and energy consumption. The primary objective is to determine whether the flow cell can achieve desirable chlorine levels under consistent operation while chloride content of water varies. Chlorine (Cl2/HOCl/OCl−), chlorine dioxide (ClO2) production, and toxic oxyanions (ClO3−, ClO4−) were assessed in a single pass setup utilizing different representative anodes including Ti/RuO2, Ti/IrO2, and Boron-doped diamond. Among these materials, the Ti/RuO2 anode emerged as the most suitable for effective chlorine generation while minimizing the formation of ClO3− and ClO4−. The performance of in situ electrochlorination using the Ti/RuO2 anode in the flow cell revealed that cross velocity exerted the most significant influence on chlorine generation, while chloride content and current density primarily impacted energy consumption. Optimization of the operating parameters illustrated that stable chlorine concentrations ranging from 2 to 4 mg L−1 could be maintained even with significant fluctuations in chloride concentration from 50 to 250 mg L−1, resulting in a daily energy consumption of less than 0.07 kWh per treated volume of 634 L (i.e., < 0.11 Wh L−1). These experimental findings hold promise for advancing electrodisinfection systems to higher technological readiness level.