A novel flow injection‐chemiluminescence (FI–CL) approach is proposed for the assay of pioglitazone hydrochloride (PG‐HCl) based on its enhancing influence on the tris(2,2′‐bipyridyl)ruthenium(II)–silver(III) complex (Ru(bipy)32+‐DPA) CL system in sulfuric acid medium. The possible CL reaction mechanism is discussed with CL and ultraviolet (UV) spectra. The optimum experimental conditions were found as: Ru(bipy)32+, 5.0 × 10−5 M; sulfuric acid, 1.0 × 10−3 M; diperiodatoargentate(III) (DPA), 1.0 × 10−4 M; potassium hydroxide, 1.0 × 10−3 M; flow rate 4.0 ml min−1 for each flow stream and sample loop volume, 180 μl. The CL intensity of PG‐HCl was linear in the range of 1.0 × 10−3 to 5.0 mg L−1 (R2 = 0.9998, n = 10) with limit of detection [LOD, signal‐to‐noise ratio (S/N) = 3] of 2.2 × 10−4 mg L−1, limit of quantification (LOQ, S/N = 10) of 6.7 × 10−4 mg L−1, relative standard deviation (RSD) of 1.0 to 3.3% and sampling rate of 106 h−1. The methodology was satisfactorily used to quantify PG‐HCl in pharmaceutical tablets with recoveries ranging from 93.17 to 102.77 and RSD from 1.9 to 2.8%.