[2] How it works is not completely clear but is believed to involve increasing the amount of sodium and water lost by the kidneys.

[1][15] A meta-analysis of randomized controlled trials found that chlortalidone is more effective than hydrochlorothiazide for lowering blood pressure, while the two drugs have similar toxicity.

[18][19][20] [21] Chlortalidone is used to treat enlargement of the left ventricle of the heart; it works chiefly by lowering blood pressure, and thereby reducing systemic vascular resistance.

[26] A Cochrane review found tentative evidence that thiazide exposure was associated with a reduced risk of hip fracture.

[27] A secondary analysis of data from the ALLHAT study found that chlortalidone reduced risk of hip and pelvis fracture.

[31] Chlortalidone reduces the endolymph volume which reduces the hydrostatic pressure in the inner ear chambers; elevated endolymph pressure in the inner ear is thought to be the cause of Ménière's disease or ’Endolymphatic hydrops.’ Synthesis of evidence from multiple small, low-quality studies indicates that chlortalidone or other thiazide diuretics are effective for Ménière's Disease.

Nephrogenic diabetes insipidus occurs when the kidney is unable to concentrate urine because it has an inadequate response to vasopressin-dependent removal of free water from the renal tubular filtrate.

[1][10] Chlortalidone reduces reabsorption of sodium and chloride primarily through inhibition of the Na+/Cl− symporter in the apical membrane of distal convoluted tubule cells in the kidney.

This can result in a low blood concentration of potassium and chloride as well as a mild metabolic alkalosis; however, the diuretic effect of chlortalidone is not affected by the acid-base balance of the person being treated.

[47] Initially, diuretics lower blood pressure by decreasing cardiac output and reducing plasma and extracellular fluid volume.

The reduction in intravascular volume induces an elevation in plasma renin activity and aldosterone secretion, further contributing to the potassium loss associated with thiazide diuretic therapy.

Due to its long half-life, chlortalidone may accumulate in newborns via breast milk, despite receiving only about 6% of the maternal weight-adjusted dose.

Chlortalidone is banned for some sports (including cricket) because it is a diuretic, and can be used to reduce body weight or to mask the concomitant use of performance-enhancing drugs.