I remember when I first tried reading Yotsuba in Japanese. I’d already read it in English, and everyone (online in general) goes on about how it’s the best thing for a beginner to read in Japanese, so I figured I’d give it a shot (even though my grammar knowledge was all over the place and lacking in a lot of areas).
Trying to read it, I failed miserably. At that point, I gave up on reading manga for a while, but didn’t know what resources were available to learn grammar well. I failed to make any grammar progress. I had been learning new vocabulary for a while, and continued to do so.
Some time later, I decided to read the whole first volume, without looking anything up. Just read and understand what I understand based on what grammar and vocabulary I did know, and what I remembered from reading it in English many years prior (not much).
The result? Not much. I didn’t get anything out of it.
This year, I upped my grammar knowledge (any N5 I was lacking, and more N4), and joined book clubs in the community here. This pushed me to start looking up grammar I didn’t know. When I returned to Yotsuba, I was able to make my way through volume one, and understood a lot of it! Grammar was the big thing, but having an increased vocabulary helped keep me from having to look up every word. While knowing kanji isn’t necessary due to furigana, being able recognize some kanji is always nice.
I’d say, give it a try. If you can’t understand it, learn more grammar and vocabulary. You can either use Yotsuba as a launching point to learn even more grammar in context of native material, or shelf it for a bit, trying again from time to time to see if the latest grammar you’ve learned elsewhere shows up in the comic.
I find there’s a good mix of very easy chapters (especially when there’s little dialogue, and most of it revolves around the kids talking) and very difficult chapters (when it’s the adults together talking, and even Yotsuba’s lost on what’s being said). Some of the easiest chapters show up in later volumes.