Pisidian Antioch was a highly significant Roman colony with a large Jewish population. On the Sabbath, Paul and Barnabas went to the synagogue and were invited to speak to the people after the readings from the Law and the Prophets. Paul gives an overview of Israel's history from the time of exodus to Samuel (vv. 17-20) and from David to Jesus (vv. 22-23). The Israelites' decision to ask for a king meant they turned their backs on God's rule. Paul refers to David as the one who would do His will. David was not without flaws, and his kingdom was divided after his death. Paul explains that Jesus is the descendant of David, sent as Israel's savior by God. The mention of John the Baptist may seem odd, but he was a transitional figure and the final messianic prophet, marking the end of an era.

Paul addresses his audience as "Brothers, sons of the family of Abraham, and those among you who fear God" and urges his listeners to convert. The gospel is now reaching Jews in Pisidian Antioch because of the rejection of Jesus by the Jews in Jerusalem, fulfilling the words of these same misunderstood prophets (Acts 13:27, 29). Paul gives hope to his audience by telling them that God fulfilled his promise to their ancestors by raising Jesus, which is good news. Jesus' sonship and kingship are inseparable since he is the royal son of David, who could not be held by death. The resurrection is not only evidence of God's promise-keeping, but it is also how we are saved. Through the resurrected Jesus, we are offered forgiveness of sins and freedom from what the law of Moses could not provide. The law cannot bring about a change of heart, and when faced with the law, it exposes the true extent of sin within the human heart. Only belief in Jesus brings freedom from the curse of sin. Paul brings his sermon to a close with a word of warning (vv. 40–41). Paul quotes Habakkuk 1:5, ending on an ominous note of prophecy concerning the failure to believe God's work "in your days … even if one tells it to you" (Acts 13:41). Luke's comments do not seem to describe conversion. Still, at the very least, these listeners are sympathetic and interested. They invite them to come back on the following Sabbath.

The following week as Paul and Barnabas were preaching about Jesus and attracting a large crowd, the Jews became jealous and started contradicting Paul. They reviled him, which is considered blasphemy. Interestingly, the Jews accused Paul of blasphemy, despite them being the ones committing it. In response to the situation, Paul announces, "We are now directing our efforts towards the Gentiles" (13:46). The Gentiles hear the good news and are filled with joy upon receiving it. Paul is recognized as the apostle to the Gentiles. However, this does not mean he excluded the Jews. Luke clarifies that this seemingly impossible feat was made possible by the preached Word, as "As many as were appointed to eternal life believed" (Acts 13:48). The Word is the means appointed by God for calling his people. Paul and Barnabas left Pisidian Antioch because the Jews there opposed them, but many believed in Jesus and became disciples filled with the Holy Spirit. Before leaving, Paul and Barnabas shook the dust off their feet as a symbolic gesture.

Iconium, a city in central Galatia, is a model for the apostles' experience of spreading the gospel message. Paul and Barnabas make their way to the synagogue, which serves as the location to share the message about how God fulfilled his promise to Abraham through Jesus of Nazareth. The believing Jews quickly stirred up Gentiles to oppose Paul and Barnabas. Despite the opposition, the two continued to stay in Iconium and preach the gospel. Additionally, the Lord's presence was evident in their preaching through the "word of his grace" (Acts 14:3), which refers to the message of salvation in Jesus. They were also able to perform "signs and wonders" by his power. When opposition turns life-threatening, Paul and Barnabas leave town. But there does not seem to be any divine warning at Iconium. Luke records that they find out about the plan of a mixed group of Gentiles, Jews, and city leaders to stone them. Like converts to the gospel, its opponents come from all social, ethnic, and political backgrounds. As Paul and Barnabas make their way through Galatia, they continue preaching the gospel wherever they go (v. 7), and in doing so, they will face further danger.