A simple zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) method was developed and applied to film-coated tablets to determine ketoprofen. Separation was performed using gradient elution with a mixture of acetonitrile and acetate buffer at an Ultraviolet (UV) detection wavelength of 255 nm on self-constructed ZIC-HILIC-1 and ZIC-HILIC-4 columns. The hydrophilicity of ketoprofen was validated by examining its behaviour with varied acetate buffer, acetonitrile proportions, and pH values. The mechanism of separation is based on ketoprofen partitioning in the hydrophobic interaction. The two available approaches are a viable alternative to the present ketoprofen separation methods. The developed ZIC-HILIC methods had an excellent precision (0.61%), linear ranges of 0.05-10 ppm, and detection limits of 0.01-0.008 ppm with a coefficient of 0.9995 0.9997 for the ZIC-HILIC-1 and ZIC-HILIC-4 columns, respectively. The methods' findings were compared to the British Pharmacopoeia procedure using statistical testing, which revealed no difference in accuracy between the methods.