R. Caro married at least three times. In his works he cites traditions in the names of his three fathers-in-law, R. Hayyim Albalag, R. Isaac Saba, and R. Zechariah Zaksel Ashkenazi, referring to each of them as "mori" ("my teacher"). While he was in Turkey two of his sons and a daughter died. He was survived by three sons, Solomon, Judah, and another (possibly Isaac), who died several years after him. According to one tradition a son of R. Caro was betrothed to the daughter of R. Isaac Luria (Ari z'l). His son Judah was born four or five years before his father's death. In R. Caro's responsa Avkat Rokhel (no. 134) there is a note, "Here the master, of blessed memory, left the paper blank. He should have added to the responsum, but was called to the Academy on High." He passed on in Safed on the 13th of Nisan at the age of 87; as a mnemonic Song of Songs 5:11 was quoted: "His head is as the most fine gold" (paz, "fine gold": numerical value 87). He was buried in Safed where his grave is still to be seen in the old cemetery.

בראש הספר הקדמת ר' יוסף קארו, "רמזי הדיני' שבטור", ו"פרטי רמזי דינים המחודשים שבספר בית יוסף". קולופון: והתהי השלמת הטור השלישי... יום ששי, ארבעה ימים לחדש תמוז שנת שי"ג, ע"י... קורנילייו אדיל קינד... וכמוהו הוטפל בהדפסתו החכם... משה אבן שושן מעיר צפת...". על שינויים טיפוגרפיים בדף עד (57 או 59 שורות), עיין: י' זנה, קרית ספר, ז, תר"ץ, עמ' 484, מס' 4.