I’m looking for colleges with the same sense of humor and quirkiness as UChi but with a less strenuous work load and less selective. Anywhere in the country but bonus points for finding one in the south. 
U Chicago is usually compared to Swarthmore for ‘Life of the Mind-ness.’ But Swarthmore’s not less selective (although the weather is somewhat better.) Reed might be a fit if the edgy, quirky and urban is your goal. Grinnell in the midwest shares the quirk factor - but it’s in very small town and the weather is no better. And the workload at both schools is can be just as intense.
To add to @N’s Mom’s excellent response, I would add Carleton in Minnesota and Haverford in Pennsylvania. They are less selective than UChicago and Swarthmore, but more so than Reed and Grinnell. Carleton is in a small town, while Haverford is in a pretty suburb of Philadelphia. While both are intellectually intense, they are also friendly supportive environments. Carleton (often thought of as the Swarthmore of the midwest) is know for being quirky yet very friendly and supportive.
I am afraid, in my experience, a high component of quirkiness with a sense of humor usually goes with an intellectually intense college environment.
I can’t think of any southern colleges that qualify, but Oberlin in Ohio also might.
Not overly quirky, but in/near city, not sports-oriented, not one dominant type of person: u of Rochester, case Western Reserve, Boston university., Emory, Clark University.
Reed, to a lesser extent Bard. St. John’s.
I think Pomona College is strong academically as U. Chicago and also very selective, too but are you talking about LAC or Research University?
New College of Florida?
Most of the schools others have mentioned above are in no way similar to UChicago.
Rhodes, in Memphis, perhaps? I’ve heard good things about Southwestern, near Austin.
Here are some of the schools my friends and I were considering/applied to besides UChicago: Oberlin, Pomona, Reed, Swarthmore, Haverford, Harvey Mudd, MIT, Occidental, St. John’s College
Rhodes (mentioned above), Davidson, Furman and Trinity University.
All in the South(ish), all small LAC’s, strong academically, but not as difficult as UChicago.
At Rhodes, they re-enact the wizards’ duel from Harry Potter atop the wooden cafeteria tables each year, and also have a class gift inside a glass case in the library that is a large mace, labelled “Break in case of Zombie Apocalypse.”
Quirky enough? 
William and Mary (my current school) fits that description perfectly! It definitely has the quirky sense of humor thing going for it and it’s in the south. Other options could include Carleton College, Reed, or St. Johns
Davidson College in NC. Scripps College and Occidental College in CA.
I agree with TomSrOfBoston. Truthfully, there aren’t many universities that are similar to U. of Chicago’s atmosphere for undergrad. That doesn’t exactly make it better or worse, but one of the things that defines the U. of C. undergrad experience is the rigor of the academics.
Maybe the OP can (re)define his / her requirements better, besides “like U. of C., but not so strenuous.” If you want strong academics but less selective, many colleges would fit the bill. Perhaps as suggested, something like Grinnell may have an intellectually stimulating culture, but not be as selective. Carleton, Swarthmore and Pomona are all somewhat similar in terms of selectivity to U. of Chicago, so they may not be great alternatives despite excellent academics.
Maybe the OP means a research university with many strong departments, (and perhaps in the midwest), but not as selective as U. of C. Then you could look at Michigan, Wisconsin; further out, maybe some U. of California campuses; for south, UT-Austin, UNC-Chapel Hill, William and Mary for smaller, etc. Also, the private Johns Hopkins is known for some quirkiness and very strong academics, but not much less selective than U. of C.
How about Rice University in Houston or Washington University in St. Louis?
The OP indicated that he or she was looking for colleges that are less selective than Chicago. I would not include Pomona, MIT, WashU, Rice, JHU, et al if the OP isn’t competitive for Chicago. I would suggest Tulane, also, although it definitely has Greek life and other features that Chicago famously lacks. Most southern colleges do. People have dubbed University of Chicago as “Where fun goes to die.” The OP hasn’t provided any stats, so we don’t know how competitive he or she is as an applicant, or which attributes are most important.
New College of Florida, Hendrix College in Arkansas are two quirky but less selective schools for the smart student in the South but I agree that no schools are really like Chicago.
Tulane, Kenyon, U Richmond, Centre College, Furman, Rhodes, Earlham, Elon, Rollins, Mercer
If the OP wants a traditional, canonical curriculum, he or she could look into the St. John’s “Great Books” colleges in Santa Fe and Annapolis.
@TomSrOfBoston then how about rather than insulting other’s suggesstions, you make yourself helpful and suggest some of your own? Why are people such assholes on this website?