Isoniazid is an antitubercular drug, widely used for tuberculosis. Owing to its importance in therapeutics, the present study aims to develop simple method for the spectrophotometric determination of isoniazid (INH). Two novel reagents, epichlorohydrine (ECH) and 4-hydroxyphenaylchloride (HPC) are used for the spectrophotometric determination of INH. Based on the nucleophilic substitution reactions of INH with EPI & HPC in basic medium, rapid, simple, inexpensive, precise, and accurate visible spectrophotometric method is proposed for the determination of INH in bulk drug and in formulations. Method involves the reaction of INH with EPI and HPC in basic medium to form yellow-colored chromogen, measuring the absorbances at 405 and 402 nm for INH-EPI & INH-HPC, respectively. The optimum experimental conditions have been studied. The absorbance was found to increase linearly with the concentration of the drug and formed the basis for quantification. The calibration graphs were linear from 2.00–22.00 μg mL−1and 20.00–120.00 μg mL−1for INH-EPI & INH-HPC, respectively. The apparent molar absorptivity and Sandell's sensitivity are calculated to be0.51×104&0.10×104 L mol−1 cm−1and 0.027 & 0.134 μg cm−2for INH-EPI & INH-HPC, respectively. The procedure is used to determine INH in pharmaceutical products. The associated pharmaceutical materials do not interfere in the measurements.