Summary Chloride (Cl−) has been recently described as a beneficial macronutrient, playing specific roles in promoting plant growth and water‐use efficiency (WUE). However, it is still unclear how Cl− could be beneficial, especially in comparison with nitrate (NO3−), an essential source of nitrogen that shares with Cl− similar physical and osmotic properties, as well as common transport mechanisms. In tobacco plants, macronutrient levels of Cl− specifically reduce stomatal conductance (gs) without a concomitant reduction in the net photosynthesis rate (AN). As stomata‐mediated water loss through transpiration is inherent in the need of C3 plants to capture CO2, simultaneous increase in photosynthesis and WUE is of great relevance to achieve a sustainable increase in C3 crop productivity. Our results showed that Cl−‐mediated stimulation of larger leaf cells leads to a reduction in stomatal density, which in turn reduces gs and water consumption. Conversely, Cl− improves mesophyll diffusion conductance to CO2 (gm) and photosynthetic performance due to a higher surface area of chloroplasts exposed to the intercellular airspace of mesophyll cells, possibly as a consequence of the stimulation of chloroplast biogenesis. A key finding of this study is the simultaneous improvement of AN and WUE due to macronutrient Cl− nutrition. This work identifies relevant and specific functions in which Cl− participates as a beneficial macronutrient for higher plants, uncovering a sustainable approach to improve crop yield. Significance Statement We have identified anatomical and cellular mechanisms altered by macronutrient Cl− levels that result in lower stomatal conductance and increased mesophyll diffusion conductance to CO2. Simultaneous improvement of AN and WUE due to macronutrient Cl− nutrition can be of great relevance for increasing C3 crop productivity.