Sometimes you spend hours and days in finding some errors that can be solved in a simple way.
Here was the problem:
I was using AjaxToolKit in one of our web applications, it was running great for a long time, until one day our client reported that the website is like a mess. When I checked out, I found out there was a javascript error saying: “ASP.NET Ajax client-side framework failed to load” and all the ajax controls stopped working.
I tried to look out for some solution on the net:
- some suggested to re-install AJAX on the server.
- some of them suggested to repair the .NET framework in the server, like (Resolving “asp.net ajax client-side framework failed to load”)
- others suggested to add some script in Web.Config, https://forums.asp.net/p/1279937/2442844.aspx
I tried all the provided solutions, but my situation was different. When i checked the web application on any local PC, it was working fine, but on the hosting server it failed. So I followed up every single page in the application, and at the end I noticed something:
Any web application without the file “global.asax” with AjaxToolKit was working fine without any error, so when i removed this file, everything went ok. Now if you ask me what was the main cause of this problem i would say nothing since there isn’t any convincing reason for this, but removing this file was the solution for this sudden error!!
In case you encountered such a problem, try this option it might be the solution for this error !!
Suha's Blog 
Hello,
I am using Asp.net 4.0 and Ajax v4.0. I am using AJAXToolKit for quick search functionality..I am getting ‘Sys’ is undefined or ASP.NET Ajax client-side framework failed to load in a ASP .NET 4.0 website..When i run my appliction on local server then everything work fine but when i access my application from NLB client server then i get this error..I check both application server IIS setting, Machin.config, Web.config..all are identical..even i try to make changes in web.config file like putting handlers, etc.. but no luck. i assume in .net4.0 there no need to change in web.config as it is already taken care by Visual Studio…i gone through many blogs and tried all combination but no luck..:(..even i restall my framework on both application..rebooted many times…pls let me know if you can help me..fast response is appriciated..thanks
Hello,
These errors are weird, and no logical reason for such errors, I think your problem can be solved from the webconfig, but do u have all the service packs installed on the server. And if you can try a simple code page with the ajax without a masterpage and run it locally on the server to test it.
Hope I can help you more.
I had the same error for past two days. finally i resolved the issue. add the following items in Managed Handler in IIS.
*.asmx
System.Web.Script.Services.ScriptHandlerFactory, System.Web.Extensions, Version=3.5.0.0, Culture=neutral, PublicKeyToken=31BF3856AD364E35
ScriptHandlerFactory
*_AppService.axd
System.Web.Script.Services.ScriptHandlerFactory, System.Web.Extensions, Version=3.5.0.0, Culture=neutral, PublicKeyToken=31BF3856AD364E35
ScriptHandlerFactoryAppServices
ScriptResource.axd
System.Web.Handlers.ScriptResourceHandler, System.Web.Extensions, Version=3.5.0.0, Culture=neutral, PublicKeyToken=31BF3856AD364E35
ScriptResource
best of luck
Thanks a lot