I have a unique perimeter strategy at the moment. I have James Harden at PG, Victor Oladipo at SG, and Anthony Morrow at SF. On defense I have Harden guarding the SF, Oladipo on the PG, and Morrow on the SG. I tried to make this work using the depth chart by placing Harden third from the top on the depth chart while playing him as the Point Guard. However Harden was guarding the Point Guard in this set-up.

The solution I found was to adjust the matchups from the strategy page before each game.
However, I wonder if it would be possible to use the depth chart by having the top player guard the Point Guard, the second guard the Shooting Guard, and the third guard the Small Forward?

No that is not possible - the depth chart is meant to be setup as PG, SG, SF, PF, C and then bench in that order. The whole reason the defensive matchup strategy was added into the game on the strategy page is exactly for what you are doing so that you can assign the matchups you want there.

Thanks for the response. The defensive matchup system is a very good solution, it just takes an extra 30 seconds to scout the opponents depth chart and set-up the strategy.
I feel like my plan is ideal based on skill sets and size.