Disadvantages in Multidexing the android application
The main drawback is a larger dex/apk size. Dex files have pools of constants that are shared among all the classes in that dex file. When classes are split across multiple dex files, these shared constants have to be duplicated in each dex file they are used in.
Multidexing itself is non-performing term, if application is multidex it means there is burden over android internal process which executes application.
Every android application runs inside a single process(task), when its multidexed, it means the process is divided into parts which going to create performance issues with small android processor, no matter how you write code.
I am agree with aakash kava that almost all applications are multidexed because now a days android processors are very good in performance and android RAM is excellent, But it does't ,mean we should ignore multidexing.
Generally spoken the disadvantages of multidex are: Increased APK size, possibly slower app startup and increased memory footprint.
The reason for that is that some data (e.g. StringData) can not be shared and therefore need to be partially stored in multiple DEX files at the same time. StringData consists of string literals loaded from code as well as class, method and field names and commonly account for up to 20% of the total DEX file.
But the actual disadvantages (beside APK size) highly depend on the Android version you are running the app on.
Google optimized the Android Runtime (ART) to remove these drawbacks. Android O (API 26) introduced the VDEX container to store pre-validated DEX files. With Android P Google further optimized the precompiler (codename CompactDex) and added an shared data section to the VDEX container to deduplicate the data used in multiple DEX files. So there are little to none disadvantage when running multidex apps on Android P runtime.
Sources: What's new in Android Runtime (Google I/O '18)
You are overthinking about multidex, instead you should observe and identify if there is any performance issue with your app by profiling your application.
Multidexing hardly increases any size of code, major size and performance issues are with animation/image/audio/video resources, they are the ones who increase size and reduce performance.
Including many third party libraries will eventually pass 64k limit and almost all applications today are multidexed, Users demand multifeatured apps today, that requires integration with many third party libraries.
Only when you are doing animation/game programming, where speed matters the most, more method calls might be harmful, but this has nothing to do with multidexing, even poorly written small non multidexing app will perform bad on any device.
Startup time will affect with multidexing, but it can certainly be improved by changing your app logic to delay loading of other costly library and resources.
Is reducing the method count worth it??
NO
Ideally you should use more methods and modularize your code, because testing and changing mobile apps is huge challenge after it is published. Debugging and removing bugs are more costly then multidex size and its impact on performance. Due to tiny screens, different brands, different UI, users get more angry on apps on phone compared to computers. Keeping up to users demand will become easier if code is divided into multiple individual tested libraries.