The key difference between a database and a spreadsheet lies in their structure and purpose. A database is designed for storing, managing, and retrieving large volumes of structured data, utilizing a relational structure for efficient querying and data relationships. In contrast, a spreadsheet is a tool for organizing, analyzing, and visualizing smaller data sets, primarily suited for calculations and simple data management. While spreadsheets can handle basic data tasks, databases provide robust functionality for scalability, data integrity, and concurrent user access, making them ideal for complex applications.