There's a reason why only Penny (Kaley Cuoco) could make Leonard (Johnny Galecki) truly happy on The Big Bang Theory. From the get-go, it was clear that the show was gearing up for a romantic relationship between the pair. Despite this, dating each other wasn't easy, especially at the beginning. But eventually, it became clear that no one was better suited for Leonard than Penny, and it had something to do with his best friend Sheldon (Jim Parsons).
Penny and Leonard were The Big Bang Theory's original love line, although Howard (Simon Helberg) and Bernadette (Melissa Rauch) got married first. Ultimately, they tied the knot together in season 9, initially through a shotgun wedding in Las Vegas, and then a proper one with all their loved ones present. However, due to the show's shifting focus, the couple's story became stagnated for several years. While they had their respective individual arcs, nothing was going on with Leonard and Penny’s married life; at one point, the sitcom even addressed this as characters themselves realized how boring they became. But this didn't have anything to do with their compatibility, it's purely a lapse in judgment from the show's creators.
Overall, Penny and Leonard were a good fit for each other. While it wasn't mutual at first, especially since the latter fell in love at first sight, over time, they became attuned with one another. Penny forces Leonard out of his comfort zone, while he balances it out by grounding her. But there's one particular reason why only Penny could make Leonard truly happy—she also loved Sheldon. Throughout The Big Bang Theory's run, Sheldon latched on to Leonard. And, despite putting him through the wringer at times, Leonard stuck with him. Leonard could've moved out of Apartment 4A every time Sheldon did something egregious, but he remained, hinting that he genuinely cared for his annoying pal. Considering this and how difficult Sheldon was, Leonard needed a partner who was at least equally concerned for his best friend, and among all of his girlfriends, Penny was the only one who came close.
When Leonard and Penny broke up, they started dating other people. For Leonard, that included Priya (Aarti Mann), Raj's (Kunal Nayyar) sister. Unlike Penny, who knew how to handle Sheldon, Priya came off a bit too harsh on him. For a while, the boys enjoyed her putting Sheldon in his place; at one point, she even convinced them to ditch the weekly schedule, forcing Sheldon to hang out with Stuart (Kevin Sussman) and Barry (John Ross Bowie), instead. But, had Leonard continued dating Priya long-term, his close relationship with Sheldon would've ultimately become a problem for them. There's a chance that Leonard would've chosen her over his best friend, which would've effectively spelled the end of The Big Bang Theory, but it's difficult to imagine that. Leonard knew that Sheldon needed him, and since he loved his best friend, it's highly unlikely that he would've abandoned the socially-inept genius.
With Penny, Leonard could maintain his relationship with Sheldon while also not being a pushover where he's concerned. Through the years, Penny had learned to effectively deal with Sheldon. She loved him, but she didn't let him get away with his bullying. In later seasons of The Big Bang Theory, this rubbed off with Leonard as well, resulting in a much healthier friendship with Sheldon.