This paper proposes a two-phase framework to operate multiple ship defense missiles against the threat of an anti-ship missile. During the preparation phase, single-shot kill probability models associated with various evasive maneuvers of the anti-ship missile are developed and used to assess the overall kill probability obtained by combined operation of multiple defense missiles. An optimization problem to maximize the total kill probability of an engagement by determining the firing times of defense missiles is mathematically formulated and solved for various target maneuvers and operational conditions, whose results are stored to generate a firing logic table. During the actual battle (engagement phase), the firing logic table is used to operate multiple defense missiles against the threat with maximum probability of interception. A ship defense case study considering important target maneuvers was conducted to demonstrate the effectiveness of the proposed operational framework.