For me it was Chaucer. (I was a double major, English and Elementary Education.) The most difficult part was learning to recite four lines of it with appropriate pronunciation.
Early Chinese history
Organic chemistry lab I.
Early Modern Europe. I just didn’t get what I was supposed to be learning in a history class, especially when there were no exams and only papers.
Home room
Vector Calculus
The Physics of Sound. Physics designed for music majors. I suck at math. I aced some other courses that were objectively harder, and got a D+ in that physics class, my lowest college grade. That class was very hard for me.
I’m weird about math. I can do pretty complicated arithmetic in my head, but I suck at anything more complicated than Algebra I. The formulas and concepts I understand when they’re being explained, but I have no luck at remembering them. I sit down to do homework two hours after calculus class, and everything from class is gone.
I was good at geometric proofs, because that was language and logic, but most other things in geometry were pretty hard for me.
Someone said it was odd that the same type of logic expressed in language I had no trouble with, but in numbers, I was lost.
I rock at papers. Classes that were all papers and no exams I was all over. Easy A. So I majored in English.
Discrete math.
Multidimensional calculus.
Never really had a difficult college class. Lest anyone think I’m some kind of pointdexter, I barely pulled out a C- in Algebra 1 and needed a tutor to get a D- in Algebra 2 when I was in high school.
That was my favorite class in college.
My hardest class was probably a toss up between stats and diff eq, where I pretty much just went through the motions or whatever this class was. I’m pretty sure it was Real Analysis. Teacher flunked the entire class…except for 1 kid. He was 16 and this was a 400 level class. The last class most of us took (well, second to last, we all had to retake it) before getting our math degrees. We all got Fs, the high school kid got an A.
Worst thing about all of this, I never used any of it and it’s all gone now.
I mean, I could probably start from Calc 1 again, but if you handed me a Calculus test right now, I wouldn’t be able to do any of it.
There were two small grad classes, neither in my major, that the professors were kind enough to let me take, and both gave me pretty good grades, more for effort than for achievement. One was Yucatec Maya language – each of us had to translate part of an 18th-century territorial document. The other was Old English, which is more akin to German than you might imagine – declensions, conjugations, deceptive cognates…I had been inspired to take it by Argentine writer Jorge Luis Borges (through his essays), who loved Old English (and had an English grandmother).
I think my hardest class as an undergraduate was either Number Theory fall of Freshman year or differential equations in the spring. The former convinced me I didn’t want to be a math major. Until then I hadn’t chosen between Math and Physics.
Differential Equations was a much more applied math course and important for physics (and still quite important for me even though I’m not in physics). But taking the course required a ton of memorizing things – something I was never good at.
Fortunately I had no foreign language requirement or that would probably have been harder.
Without a doubt, Physical Chemistry, or P-Chem. It really should have been called Chemical Physics, but then would have probably had to have been taught by the Physics Department. Calculus, even multidimensional, was a piece of cake. Organic Chemistry, yeah, tough, but most of it was memorizing. Differential equations, pretty bad, even indeterminate ones, but P-Chem takes the cake.
I would have said Advanced Matrix Algebra, but I didn’t pass that one.
Eastern Metaphysics and Quantum Mechanics
Man, that was a WEIRD course. It was taught by a zen master and a physics professor.
Organic Chemistry II
I made a “C” in Organic I (the first “C” I ever got in my life at any level.) And that was because the professor was being generous. Needless to say, I was not all that prepared for Organic II.
I really did try. I got a “50” on my first exam, but figured that was ok b/c I could drop one test score. I spent hours studying, but I never understood the materials–not even enough to get by. But I refused to drop the class. Dropping was for quitters.
My second exam, my score was an “8.” Just so there was no mistake, the professor wrote out the word “EIGHT” and circled it. Twice. Now that “50” was looking pretty good!
I theorized that if I scored in the 70s on the final, I could drop the 8 and squeak out of there with another “C.” My theorizing was about as accurate as my Organic Chem skills. My final exam was in the '30s. I actually received a “D” in the course, perhaps because my professor was fascinated by my combination of cluelessness and stubborness. I did get “B” in the lab, however.
I re-took Organic II lecture at the satellite campus in my hometown during the summer, and got a “B.” Small class; good prof.
It did prompt me to change my major from pre-med/Chemistry to pre-med/Zoology. That put me in the crosshairs for the most *challenging *class I ever took – Comparative Anatomy. Got an “A” in that one. One of only two in the class. 
Latin. Not because it was inherently difficult, but because the amount of work required. I was used to the lazy student’s short bursts ahead of papers and tests, but Latin required a sustained effort throughout the term, with no slacking off because the knowledge was cumulative.
For those who haven’t done Latin, there’s a certain amount of educated / context-based guessing you can do with French or Spanish or German that simply doesn’t work with Latin.
That experience was extraordinarily valuable.
Integral transforms in grad school. Ruined my 4.0 for my Masters.
Advanced calculus.
I’m great with math, until we got to advanced calculus.
In my graduating year I got a “D” and I’m not sure how I even got that lucky.