Has the sign of taking up serpents (see Mark 16: 18) ever been fulfilled?

   The assumption in the question is that because we have no record in Scripture of such an event taking place then that means that it did not take place. This is without foundation. Now in a general way, the apostles (and possibly others, such as the seventy - see Luke 10: 1) were given similar divine protection in the testimony of the kingdom in Mark 16: 17, 18 - to what they, and the seventy, had enjoyed before the Lord’s death. Then He had told them: “Behold, I give you the power of treading upon serpents and scorpions and over all the power of the enemy, and nothing shall in anywise injure you” (Luke 10: 19). This verse speaks of not only physical protection but spiritual power over the enemy as well, that “ancient serpent who is [the] devil and Satan” (Rev. 20: 2). Nonetheless, the exercise of this spiritual power, of which the physical power was but a sign, does not in any way mean that the disciples did not actually take up physical serpents. That their physical protection was not absolute, however, is shown by the death of James (see Acts 12: 1, 2). A similar limited protection will be afforded to the two witnesses in Rev. 11: 3 - 12.

   Now of the five signs of Mark 16: 17, 18, four are definite (“they shall …”) allowing no uncertainty, but the matter of drinking poison is indefinite or put as accidental (“if they should …”). That is, if they accidentally happened to drink anything that was harmful, they would be protected; if they did not, such protection would of course not be needed. With the other four signs, there is no such uncertainty––they all took place. It also follows that the incident of Acts 28 cannot be a fulfilment of “they shall take up serpents” because it was accidental. Paul did not take up the viper, it “seized his hand” (v3) and He “having shaken off the beast into the fire, felt no harm” (v5). The viper initiated the action, not Paul! So we have no incidents in the NT that fulfil two of the five signs. However, that does not mean that they did not take place - though in the sign of drinking poison, because it is introduced by “if …” we do not actually need a fulfilment. With the other four signs, their fulfilment is unquestionable. The Lord said “they shall cast out demons” (Mark 16: 17) and we have a record of its fulfilment (see Acts 5: 16); the Lord said “they shall speak with new tongues” (Mark 16: 17) and they did (see Acts 2: 4 - 11); the Lord said “they shall lay hands upon the infirm, and they shall be well” (Mark 16: 18) and it took place (see Acts 3: 7); the Lord said “they shall take up serpents” and they did - even though the Holy Spirit has not been pleased to give us the record of a single incident.
It did take place because the Lord said it would. Let us pursue this a little further.

   The signs were given to confirm the testimony of the apostles to the Jews that Jesus was the Messiah and that if the nation repented, the Lord would return and establish the Kingdom on earth in power (see Acts 3: 17 - 26). The signs belonged to the Jew in connection with the Kingdom and had nothing whatsoever to do with the Church. Now this sign of taking up serpents would have a peculiar significance for the Jew. His mind would go back to the great apostle of that nation - Moses. He would recall that God had given three signs to prove that He had appeared to Moses and had sent him. What was the first of these signs? Moses was to throw down his staff and it would become a serpent. He then “stretched out his hand and caught it, and it became a staff in his hand” (Ex. 4: 4). This same sign of taking up serpents would likewise authenticate the apostles and their testimony to the Jews. We must not reason from the fact that we do not have an example of its occurrence that it did not take place. The Lord’s word was clear and definite: “they shall take up serpents” and hence it did take place.

   Finally, we live in a day when men claim to do some of the signs of Mark 16 and there are even some “who say that themselves [are] apostles and are not” (Rev. 2: 2). If a claim is made to do the signs of Mark 16, then all the signs must be claimed, not just some. Is this the case? Hardly! There are multitudes who assert that they can speak with tongues; there are plenty who claim to cast out demons; and there is no lack of those who say that they can heal the sick. However, it must strike any thoughtful person how odd it is that there is a distinct lack of those who claim to take up serpents. Why is this? Excuses can always be found for any failure in healing or casting out demons, and ungrammatical gibberish will do for speaking with tongues, but in the matter of taking up of serpents, failure results in the death of the claimant. Hence the dearth of those who can take up serpents!