A balanced pH is important in maintaining the homeostasis of the human body. However, in disease conditions, the pH of affected tissues and interstitial fluids can deviate from normal due to infection, inflammation, and hypoxia. Neutrophils, the most abundant type of white cells in the body, infiltrate areas of inflammation and fight infections through the release of neutrophil extracellular traps (NETs), which uses the neutrophil’s own nuclear material to trap and kill pathogens. Recent studies have shown that the release of NETs is mediated by extracellular pH conditions, with alkaline conditions promoting NET release. While neutrophil activation can help combat microbial infections, excessive NET release can also lead to undesirable effects, including thickening alveoli mucus in cystic fibrosis and increasing inflammation in autoimmune diseases. Disease conditions lead to pH changes in tissues and bodily fluids, dysregulating NET release. Increased NETs can clog the ducts and canals and can in turn exacerbates pathological effects (e.g., Pancreatitis). Hence, regulating pH in affected areas can be an easy and cost-effective way to optimize NET release and thereby improve disease outcomes. Here, we will discuss the physiological and pathological pH of blood and tissues, the methods of pH regulation in the body, the role of pH in neutrophil activity, as well as potential therapeutic regulators of pH (e.g., tris-hydroxymethyl aminomethane (THAM); bicarbonate, HOC3; Carbonic anhydrase inhibitors). These are clinically approved compounds, and may be useful for regulating pH at specific loci, or systemically, in certain disease conditions.