The best anything is relative. Everything depends on other factors.
The best best defense, of course, is not to be there: avoid likely bad places, avoid bad people, learn to see trouble approaching and step out of the way.
In a real ambush, the initial defense has to be trained to reflex. It must be a conditioned response that is simple and effective for a wide variety of attacks. It must disadvantage the threat and advantage you. It must be paired with realistic and appropriate stimuli. It can not be complex and it won't work in the later stages of a fight and is unlikely to work outside of an ambush- it's hard to plan to use a reflex.
So in this context, I'm talking about the best defense after it's too late for the real best. Follow me?
The point of a defense is to stop him from hurting you. One of my preferences is to make him want to do something else. Palm heel to the face.
He swings a punch, palm heel to the face. He reaches to grab, palm heel to the face. He starts to kick, palm heel to the face. I can show you the mechanics of how a center-line strike spikes most attacks, how by controlling your own elbow you can cut the line even on a centerline strike from the threat... but that's window dressing. The simple fact is that most people will abort their attacks to save their faces from impact. It stops him from hurting you by making him decide not to be hurt himself.
So what does this do? Primary purpose, prevent damage to you. But it also does damage to the threat, can better your position if you follow it up with footwork and, most importantly, it is an action. It steals initiative. With one move you have gone from passenger to driver.
It's a simple example but an easy one. Easy to demonstrate, easy to convince yourself of how well it works, easy to trust.
I prefer 'entries' (irimi), being an infighter and classically trained in jujutsu. These are a combination of movement and structured position that tend to damage and unbalance the threat, bring you to halitosis range and blow through most attacks safely. They give me everything I want, plus putting me in charge and doing so at a range that very few people really know how to fight from.
The thing about both of these attacks is that even more than physical domination (or reversal of domination) they disrupt the attacker's OODA loop. They directly attack his decision making process and freeze his mind.
This continues once you have closed to combat range by constant aggressive action. We used to call this the "flies on shit" or "stink on shit" technique... ( classical jujutsu training, yeah, but I was raised redneck). Constant action with knees, feet, hands, elbows and head, an overwhelming flurry of damage, lots of it aimed at the face. Overwhelming is the key word. I've done this without contact and had the threat freeze because all of that incoming was too much information to assimilate and respond to. That's cool.
And this, at close range or in a clinch, crosses into the realm of core fighting.
Core fighting is the ability to deal with your opponent as a unit. Legs and arms are connected through the shoulder girdle, pelvis and spine. Pressure on an arm or shoulder can prevent or force the movement of a foot. Pressure on the knee, shoulder, hip or spine can abort a punch. The combination of constant aggressive pressure that not only damages but also unbalances and immobilizes is, IMO, the best defense at this stage of conflict
There you have it. The thoughts of an aggressive infighter on defense.