Salesforce Email Delivery Error '421 4.4.0 No MXs for this domain could be reached at this time'

This error occurs in a few different situations, and some of the key considerations are:

1. The FQDN of the email relay host or MX record supplied in Email Relay settings in Salesforce has traffic from the Salesforce MTAs routed incorrectly due to internal email routing on the LAN containing the host.
2. Front-end Spam filters, perimeter Firewall, or other on the LAN the Relay host/s is on is blocking traffic from the IPs of the relaying Salesforce MTAs
3. The email relay settings in the Salesforce application specify a Port Number that differs from the Port that is open to the Relay Host on its LAN

To check Email Relay settings in Salesforce to verify the host/MX record and ports, navigate to Setup and search for Email Relay.  Correlate these settings with the Firewall, Filters, Routing, and ACLs on your local LAN.
 

• In Salesforce Classic: Setup | Email Administration | Email Delivery Settings | Email Relays
• In Lightning Experience: Gear icon | Setup | Email | Email Delivery Settings | Email Relays