Non-steroidal anti-inflammatory drugs are effective in managing inflammation but may cause gastrointestinal adverse effects. Pandanus amaryllifolius Roxb. has been reported to possess anti-inflammatory potential. This study aimed to formulate and optimize the ethyl acetate fraction of P. amaryllifolius Roxb. leaves into a fast dissolving film (FDF) and evaluate its physical characteristics and anti-inflammatory activity. The formulation was optimized using a mixture D-optimal design with HPMC and sorbitol as formulation components. The optimized FDF was evaluated for physical characteristics and anti-inflammatory activity using the human red blood cell membrane stabilization method. The optimum formulation consisted of HPMC and sorbitol at a ratio of 6:6, with a desirability value of 0.702, and exhibited acceptable physical characteristics. The ethyl acetate fraction showed higher hemolysis inhibition descriptively; however, one-way ANOVA indicated no significant difference among treatment groups (F = 0.673; p = 0.545). The ethyl acetate fraction of P. amaryllifolius Roxb. leaves can therefore be formulated into an FDF with acceptable physical characteristics and potential anti-inflammatory activity.