For a total of 15 seasons, Supernatural is without a doubt one of the best and most beloved sci-fi television shows ever made. It mixes comedy, drama, horror, and fantasy into one television series and grabbed onto fans all over the world, as it progressed. The show was so popular that some viewers were throwing around the idea that a Supernatural movie should carry on the torch, while others aren't quite so sure. With that said, even though fans loved the Dean and Sam for their sassy remarks, they also know that the Winchester boys didn't have a good track record when it came to personal relationships; after all, it was a little difficult with never staying in one spot and being demon hunters, naturally.
When the brothers, specifically Sam, did manage to have some sort of romantic relationship with a woman, it almost always ended in tragedy, death, or sometimes, the realization that the woman was a monster in disguise; literally. While Sam did some pretty shameful things on the show, there were only a few women that could trick Sam into romance, before exposing their "true" selves to him.
Amy Pond
Starting it off is Amy Pond. Amy and Sam met each other when they were teenagers after Sam saved Amy from a group of boys hassling her. Afterward, when Amy was treating Sam's wounds, they connected on a romantic level and shared their first kiss together. When Amy's mother found out Amy was hiding Sam, she went ballistic and tried to rid of him, but Amy stepped in and killed her. It wasn't under later, in season 7, that Sam and Dean found out that Amy is a Kitsune, a fox-like version of a werewolf with powers and the ability to take human form.
While Sam should've killed Amy, he couldn't do it after she saved his life when they were younger. Amy had ulterior motives for killing others, because of her son, but it didn't sit right with Dean and he ended up taking her life. As fans will remember, this caused a minor rift between the Winchester brothers, but they eventually got over it. Dean kept quite a few secrets from Sam, but this one needed to be taken care of.
Madison
Madison originally resided in San Francisco and was a secretary of a lawyer. It's important to note that Madison wasn't always a werewolf; she was bitten by one and turned into one. The culprit was Glen, her next-door neighbor who had a crush on her. While she was previously in a relationship with a possessive and abusive man named Kurt, she later told Sam that the mugging she experienced, which was actually Glen, gave her the strength to end her relationship. Madison was unaware that she actually turned into a monster when her human form fell asleep and would only attack those that were a threat to her subconscious form; which is why Sam was unharmed as he lied next to her.
It wasn't known for a while that Madison was a monster and was even interviewed by the Winchester boys after killings started happening around the area. It was actually luck that Sam and Madison started a relationship because the Dean and he flipped a coin to see who would protect her. Once Madison went after Kurt as a werewolf, Dean caught her in the act and cut her arm, which would stay when she returned to human form. As Madison pleaded with Sam to not hurt her, he complied. After realizing a cure wasn't going to happen, Sam ended Madison's life after she said she didn't want to live as a monster.
Ruby
When it comes to Ruby and Sam, they without a doubt, have one of the most difficult and complex relationships on the show. Initially allies again Lilith, it was a mystery as to why Ruby had an interest in the Winchester boys until the end of season 4. Ruby knew Sam was the last surviving special children that Azazel had plans for, which interested her. While Ruby watched Sam before meeting him, he finally caught on and approached her. After Sam was confronted by three demons, Ruby stepped in and helped, which prompted him to trust her a little. While it seems like Ruby knew all about Sam, he was still in the dark about her intentions and plans. Even though she revealed herself as a demon, Sam doesn't completely recoil and take care of the issue. She claims she can help him with Dean and he spares her life.
Their relationship didn't fully take off until Dean's incarceration in Hell and Sam was addicted to demon blood, with the help of Ruby. Throughout the series, she always seemed like she had something up her sleeve, but somehow, their relationship turned romantic in season 4. While Sam doesn't want to become intimate with a demon, Ruby assures him it's okay. Beyond this point, it's clear how malicious she is and that Dean knows something is up with her. After succumbing to Ruby and her tricks, Sam and Dan finally take her out her with her own knife. She's not really dead though and in season 15, reminisces about her feelings for Sam. In the alternate reality bit of the series, Sam finds out he is married to "Ruby" - actually being actress Genevieve Cortese and reminisces on the terrible experience he had with the real Ruby, played by Katie Cassidy. Somehow, this "Ruby" catches Sam's eye and brings him upstairs.
Whichever version of Ruby, she did some incredibly evil things on Supernatural, but still won over Sam. Ruby also had her moments, and was underrated at times, but was a pivotal character to the show. This portion of the series also made fans realize Sam's character might be getting worse, in comparison to the beginning of the show.
Meg Masters
The first time Meg and Sam met, they were both on their way to California. Even though Sam was supposed to be a demon hunter, he didn't pick up on the fact that Meg was a demon working for Azazel and was possessing a girl to get closer to him. It didn't take long for them to get to know one another, even though all she wanted to do was kill Dean and Sam. After Sam picked up on something not right about her, she still tricked him into thinking she was incredibly attracted to him, and even before she was killed by Sam, told him she could be useful when finding John.
After freeing the demon from the woman's body, it possessed Sam for a short time and eventually, came back in another body in the Apocalypse. Dean, Sam, and the new Meg Masters fought together against Crowley, even though they didn't trust Meg completely. It was when Meg helped Sam seal the Gates of Hell, knowing she'd be trapped with the other demons as well, earned Sam's trust. She was eventually killed by Crowley, while Sam watched with horror.