This complex interface has two layers, both of which are complex in themselves. A primary and secondary layer if you like. Using a popup is a good start but there are several ways you can make this easier to use:
Highlight the cell that they are operating on and consider using that as the trigger to open the popup, or highlight and the enter key, meaning you won't need an icon, a simple instruction in the header will cover all cells, following on from that:
Keyboard navigation - using arrow keys (and tab) to move around and enter to trigger the secondary popup - and esc to close it, along with cell highlighting so the user knows which cell will trigger a popup. Enter to examine and esc to close is a very common pattern in software, gaining great recognition as a result of Spreadsheet software.
Provide complete interaction from mouse and keyboard - especially if this is going to be heavily and repetitively used. highlight would equate to one click and highlight and enter would equate to a double click. Remember, your mouse interactions double up as taps on touch screens (this doesn't look like a phone app, at least in it's current form, but tablet sized screens would handle it).
Allow navigation from secondary layer to secondary layer, so you would be able to move around the cells but have the secondary layer popup and focus automatically without going back to the grid. If you decided to popup on focus then this would naturally happen each time the user moved amongst cells.
Use a fixed child UI layout as suggested by JayFang in their answer - this is probably better than a central popup or other sorts of popup (credit due to JayFang for this suggestion, but in order to make my answer as complete and good as possible I had to think and make use of this knowledge)
Search / filter facility - allow the user to quickly restrict cells using typed search terms, for example, 5b9 would immediately focus on that cell and you can then either open the popup immediately or focus on it so their next keypress opens the secondary level of interaction.
Highlight the current row and column they are on at the interface edges, much in the way that excel does, providing extra feedback to their position and also helping them deduce what is contained by any cells obscured by the popup
Examine your users - are they experts - if so, you can afford to sacrifice a certain amount of discoverability in order to make things more streamlined and rely on the fact that expert users will invest time in learning and teach each other. There's a big difference between facebook or google, building a learnable interface for a billion users and an application targeted at a few experts.
Highlight the first cell on page load - marking your instruction up in a similar way will help the new user make the connection
two screen solution - as you mention that the secondary level of interaction is complex too (a grid of 5 by 6, presumably editable, fields) you could also consider splitting it off onto its own screen and gaining the benefits of a full screen for this secondary grid. Retain grid context clearly and provide secondary layer to next secondary layer navigation too
You might not need to implement all of this to provide a good solution, but you should be able to play around with these different ideas, build a few prototypes, combine a bit of user observation with some hands on user testing and find the best pattern for your specific application.
PS don't just use colour to highlight