Automating real E2E user flows with Appium on Android devices presents several challenges, including handling multiple browsers and webviews, dealing with different ChromeDriver versions, and navigating welcome screens. To overcome these challenges, developers can use various strategies such as executing adb shell commands to hide or show welcome screens, using try/catch blocks to handle notification scenarios, and waiting for specific contexts or webviews to appear. By employing these techniques, developers can create robust scripts that successfully automate real E2E user flows on Android devices with Appium.