Optimized orally disintegrating tablets (ODTs) containing furosemide (FUR) were prepared by direct compression method. Two factors, three levels (32) full factorial design was used to optimize the effect of taste masking agent (Eudragit E100; X1) and superdisintegarant; croscarmellose sodium (CCS; X2) on tablet properties. A composite was prepared by mixing ethanolic solution of FUR and Eudragit E100 with mannitol prior to mixing with other tablet ingredients. The prepared ODTs were characterized for their FUR content, hardness, friability and wetting time. The optimized ODT formulation (F1) was evaluated in term of palatability parameters and the in vivo disintegration. The manufactured ODTs were complying with the pharmacopeia guidelines regarding hardness, friability, weight variation and content. Eudragit E100 had a very slightly enhancing effect on tablets disintegration. However, the effects of both Eudragit E100 (X1) and CCS (X2) on ODTs disintegration time (Y1) were insignificant (p > 0.05). Moreover, X1 exhibited antagonistic effect on the dissolution after 5 and 30 min (D5 and D30, respectively), but only its effect on D30 is significant (p = 0.0004). Furthermore, the optimized ODTs formula showed good to acceptable taste in term of palatability, and in vivo disintegration time of this formula was about 10 s.