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According to mental floss:

According to Patrick Smith, former airline pilot and author of Cockpit Confidential, a flight number is technically a combination of numbers and letters prefaced by the carrier’s two letter code—Delta is DL, United is UA, and American is AA, etc.

Typically, flights going eastbound or north are assigned even numbers, and those headed west or south get odd numbers (there are exceptions to this rule, though). Return flights between destinations are often assigned a number that is one higher/lower than the outbound flight. So, if you were flying roundtrip from Philadelphia to St. Maarten, U.S. Air flight 1209 would take you down to the Caribbean (southbound) and flight 1208 would bring you back to the States (northbound).

In general, the lower the number, the more “prestigious” the flight route is for that particular airline. One or two-digit numbers are typically assigned to popular routes—usually of the long-distance variety—such as United Flight 44 from Newark to London. If you find yourself on a flight with a low number, it’s a pretty safe bet that your flight is a regular moneymaker for the airline.