Accurate, sensitive, and precise RP-HPLC methods were developed and validated for determination of Methocarbamol and its related substance (Guaifenesin) in two ternary mixtures with Ibuprofen and Diclofenac potassium. The first mixture containing Methocarbamol, Ibuprofen, and Guaifenesin was separated using Isocratic elution on a Phenomenex C-18 column using 0.05 M KH2PO4 (pH = 7): acetonitrile methanol (90:25:15, by volume) as a mobile phase at a flow rate of 1.2 mL.min(-1) and UV detection at 220 nm. The second mixture containing Methocarbamol, Diclofenac potassium, and Guaifenesin was separated using Isocratic elution on a Phenomenex C-18 column using 0.05 M KH2PO4 (pH = 7): acetonitrile (80:30, v/v) as a mobile phase at a flow rate of 1.5 mL.min(-1) and UV detection at 278 nm. The proposed methods were successfully applied for determination of Methocarbamol, Ibuprofen, and Diclofenac potassium in presence of Methocarbamol related substance (Guaifenesin) either in bulk powder or in its pharmaceutical formulation.