The key differences between Microsoft Dynamics 365 and Salesforce are in their architecture, integration, and customization. Dynamics 365 combines CRM and ERP, offers both cloud and on-premises deployment, and integrates seamlessly with Microsoft products like Office and Azure. Salesforce operates on a multi-tenant cloud, excels in third-party integrations via AppExchange, and has a user-friendly interface. Dynamics 365 is typically more cost-effective for medium to large businesses, while Salesforce offers competitive pricing for smaller businesses.